PIP3 activates AKT signaling (Homo sapiens)

From WikiPathways

Revision as of 09:28, 26 July 2016 by Ryanmiller (Talk | contribs)
Jump to: navigation, search
17126, 118, 17854, 728374, 8674, 86, 139193, 20474, 8676, 8411319913964, 93, 135, 14974, 86, 13975, 179149431, 533776, 84, 10996, 1092131140, 17022, 29, 35, 69, 10378, 19596, 10916411, 21, 14731, 531793, 100, 168, 18257, 67, 116, 142, 18833, 39, 43, 70, 81...891391, 42, 6663, 71cytosolnucleoplasmPPP2CA p-Y546,Y584-PTPN11 PIP4K2B PI(3,4,5)P3 MLST8 PDPK1 TP53 Tetramer:PTENGenePDGFB(82-241) p-5Y-FGFR4 PI(3,4,5)P3 TSC2GAB1 p-T145-CDKN1A Activated FGFR2c homodimer bound to FGF Signalling by NGFATPPIK3R1 p-11Y-PDGFRA EIF2C2 p-Y63,Y79,Y110-TRAT1 ATPPX-866 PI(3,4,5)P3 PPP2R1A PPP2CB Signaling by ERBB2p-T202,Y204-MAPK3 2xHC-INS(25-54) PI3K inhibitorsSignaling by PDGFp-T-AKTLY294002 p-S21-GSK3A FGF19 EIF2C1 NRG2 FGF3 FGF16 PPP2R1B PP2A-B56-beta,gammaPDPK1 Mn2+ p-S15,S356-RPS6KB2p-T185,Y187-MAPK1 p-12Y-PDGFRB PI5PPPP2R1B Activator:PI3Kp-S473-AKT1 FGF17-1 AKT2 TRIB3 ATPPHLPP (Mn2+cofactor)FOXO3 PPP2R1A PIK3R2 Signaling by the BCell Receptor (BCR)Activator:PI3K AKT1 E17K MDM2p-S-AKT:PIP3p-Y419-SRC-1 PTEN mRNA Costimulation by theCD28 familyPPP2CA GSK3B EGF-like ligands PIK3CD FGF4 TNRC6C MAPKAP1 PPP2R5C PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersp-7Y-KIT BGT226 PIP5K1B FGF18 MOV10 FOXO4-2 Activated FGFR2b homodimer bound to FGF TNRC6A PI(3,4,5)P3 PI3K mutants AKT1 E17K BADp-S133-CREB1PIP4K2C FGF10 p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform perifosine CD86 IER3IER3 FGF8-1 KLB p-T308,S473-AKT1E17KAKT1 PDPK1FGF22 p-T202,Y204-MAPK3 p-S368-PPP2R5B p-6Y-FRS2 PPP2R1B INSR(28-758) p-S337-PPP2R5C p-S9/21-GSK3miR-26A1 p-T23-CHUKPP2A-A:PP2A-CPI(4,5)P2 ATPEIF2C4 FOXO1,FOXO3,FOXO4AKT:PIP3PTEN:Mg2+PDPK1:PIP2PPP2R5A CDKN1A/BIntrinsic Pathwayfor ApoptosisBKM120 PDPK1:PIP3PPP2R1A perifosine EGF EIF2C1 Signaling by FGFRFYN p-6Y-INSR(763-1382) p-T185,Y187-MAPK1 PPP2R5E AKT inhibitors:AKTTNRC6C p-T305,S472-AKT3 AKT3 H2OSignaling by SCF-KITPPP2CB p-S473-AKT1 E17K AKT NR4A1MTOR PPP2R1A EIF2C3 ADPPIK3CA p-6Y-FGFR3b PDPK1 AKT1 THEM4 PTEN mRNA:miR-26ARISCKITLG-1(26-190) p-Y-IRS1 ADPp-S473-AKT1 TP53 TetramerActive AKTp-S166,S188-MDM2CHUKCASP9(1-416)PI3Kmutants,Activator:PI3Kp-T305-AKT3 PPP2R5E p-T308-AKT1 KL-2 PIP4K2 dimersPI(3,4,5)P3PiAKTATPPP2AActivatedSRC,LCK,EGFR,INSRp-8Y-FGFR1b p-Y307-PPP2CA LCK p-T309,S474-AKT2 H2Op-S473-AKT1 E17Kmutant:PIP2THEM4/TRIB3p-T308,S473-AKT1 p-T309,S474-AKT2 PTEN p-6Y-EGFR VAV1 TP53 AKT:PIP3:THEM4/TRIB3GDC0941 Active AKTTriciribine p-Y-IRS2 p-S9-GSK3B p-S939,T1462-TSC2p-S197,S262,T32-FOXO4 p-T308,S473-AKT1 XL765 PHLPP2 BEZ235 PI(4,5)P2 THEM4 p-T309-AKT2 PDPK1 miR-26A RISCPPP2CA p-T32,S253,S315-FOXO3 H2OXL147 PPP2R5B ATPPDGFB p-T24,S256,S319-FOXO1 Triciribine AKT3 NRG1 wortmannin p-T308,S473-AKT1Signaling by EGFRPIP5K1C ADPSignaling by ERBB4XL147 FOXO4-1 4xHC-INS(90-110) PPP2CB wortmannin PPP2R5D CDKN1A ADPp-Y307-PP2API(3,4,5)P3 MK2206 miR-26A1 GRB2-1 CREB1ADPPPP2R5B CD80 Neuregulins PHLPP1 GRB2-1 TNRC6A EIF2C2 p-FOXO1,p-FOXO3,p-FOXO4PIK3R1 EIF2C3 p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform FGF5-1 p-6Y-CD19 CDKN1B TP53 RegulatesMetabolic GenesFGF23(25-251) PDPK1:p-S473-AKT1E17K mutant:PIP2AKT1 E17Kmutant:PIP2p-Y307-PPP2CB RAF/MAP kinasecascadep-S351-NR4A1FGF6 miR-26A2 p-Y,Y877-ERBB2 PPP2CB RPS6KB2MK2206 PI3K mutants p-T32,S142,S207-FOXO4-2 PRR5 PPP2R5C EIF2C4 BKM120 PDGFA-1 PX-866 FGF2(10-155) PPP2R1B PPP2R5A ATPPIP4K2A PPP2R5B ADPp-8Y-FGFR1c miR-26A2 BEZ235 p-S472-AKT3 AKT1 p-7Y-ERBB2 AKT1 E17K AKT1S1KL-1 GalNAc-T178-FGF23(25-251) TNRC6B p-S473-AKT1 E17K p-T-CDKN1A/BFGF20 p-S474-AKT2 p-10Y-ERBB3-1 PI(4,5)P2ADPPPP2R5D p-6Y-ERBB2 GDC0941 AKT1FGF1 PPP2R5B ATPPip-T157-CDKN1B p-6Y-EGFR Mg2+ p-S99-BADPTEN Genep-Y191-CD28 AKT2 PTEN Gene PPP2R5C PPP2CA PIP5K1A p-S196-CASP9(1-416)ADPMitotic G1-G1/SphasesGSK1059615 p-T305,S472-AKT3 AKT BGT226 ADPPIK3R3 LY294002 p-S472-AKT3 TORC2 complexRICTOR PiPIK3CB PI(4,5)P2 AKT3 Activator:PI3K FGF9 TP53 AKT/AKT1 E17K mutantPI4PPDGFA-2 EGF GSK3p-Y394-LCK AKT1 E17KPIP5K1A-CHS p-Y-ERBB2 FOXO1 p-S-AKT:PDPK1:PIP3PPP2R5C TNRC6B PPP2R1B p-S474-AKT2 p-S368-PPP2R5B,p-S337-PPP2R5CPI3K Inhibitors:PI3KATPATPMOV10 TRIB3 AKT2 PTEN mRNAXL765 p-T,Y MAPK dimersGSK1059615 p-6Y-FGFR3c p-S183,T246-AKT1S1GSK3A PPP2R1A AKT inhibitorsPI(4,5)P2 ADP153977, 91, 15174641141347, 108, 192136, 15616, 28, 30, 34, 38...93747498259339, 98, 114, 123, 135...7416517, 4432, 68, 90, 117, 128...6496, 1099815123, 20314914974254995, 144, 20518, 20, 40, 52, 175...36, 46, 82, 88, 106...1147418616539135135642249123, 2032, 23, 146, 15918621744, 6-8, 10...5, 9, 12, 21, 24...136, 156


Description

Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. View original pathway at:Reactome.

Comments

Reactome Converter 
Pathway is converted from Reactome id:

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Marino M, Ascenzi P.; ''Steroid hormone rapid signaling: the pivotal role of S-palmitoylation.''; PubMed Europe PMC Scholia
  2. Heldin CH, Ostman A, Rönnstrand L.; ''Signal transduction via platelet-derived growth factor receptors.''; PubMed Europe PMC Scholia
  3. Chen J, Martin BL, Brautigan DL.; ''Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  4. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMed Europe PMC Scholia
  5. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  6. Kunkel HG.; ''Surface markers of human lymphocytes.''; PubMed Europe PMC Scholia
  7. Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, Vande Woude GF.; ''Mechanism of met oncogene activation.''; PubMed Europe PMC Scholia
  8. Yim EK, Peng G, Dai H, Hu R, Li K, Lu Y, Mills GB, Meric-Bernstam F, Hennessy BT, Craven RJ, Lin SY.; ''Rak functions as a tumor suppressor by regulating PTEN protein stability and function.''; PubMed Europe PMC Scholia
  9. Cai J, Fang L, Huang Y, Li R, Yuan J, Yang Y, Zhu X, Chen B, Wu J, Li M.; ''miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer.''; PubMed Europe PMC Scholia
  10. Shen Y, Naujokas M, Park M, Ireton K.; ''InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  11. Beenken A, Mohammadi M.; ''The FGF family: biology, pathophysiology and therapy.''; PubMed Europe PMC Scholia
  12. Kainulainen V, Sundvall M, Määttä JA, Santiestevan E, Klagsbrun M, Elenius K.; ''A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis.''; PubMed Europe PMC Scholia
  13. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  14. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W.; ''Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization.''; PubMed Europe PMC Scholia
  15. Rodrigues GA, Falasca M, Zhang Z, Ong SH, Schlessinger J.; ''A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling.''; PubMed Europe PMC Scholia
  16. Chen TH, Chan PC, Chen CL, Chen HC.; ''Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition.''; PubMed Europe PMC Scholia
  17. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.; ''Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.''; PubMed Europe PMC Scholia
  18. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA.; ''Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product.''; PubMed Europe PMC Scholia
  19. Fu SM, Winchester RJ, Kunkel HG.; ''Similar idiotypic specificity for the membrane IgD and IgM of human B lymphocytes.''; PubMed Europe PMC Scholia
  20. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  21. Beviglia L, Kramer RH.; ''HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells.''; PubMed Europe PMC Scholia
  22. Wang D, Li Z, Messing EM, Wu G.; ''Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM.''; PubMed Europe PMC Scholia
  23. Wienands J, Freuler F, Baumann G.; ''Tyrosine-phosphorylated forms of Ig beta, CD22, TCR zeta and HOSS are major ligands for tandem SH2 domains of Syk.''; PubMed Europe PMC Scholia
  24. Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS.; ''STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1.''; PubMed Europe PMC Scholia
  25. Lin CH, Liu SY, Lee EH.; ''SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1.''; PubMed Europe PMC Scholia
  26. Handa RJ, Ogawa S, Wang JM, Herbison AE.; ''Roles for oestrogen receptor β in adult brain function.''; PubMed Europe PMC Scholia
  27. Brognard J, Sierecki E, Gao T, Newton AC.; ''PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms.''; PubMed Europe PMC Scholia
  28. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, Riisnaes R, Pope LL, Heaton SP, Thomas G, Garrett MD, Sullivan DM, de Bono JS, Tolcher AW.; ''First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.''; PubMed Europe PMC Scholia
  29. Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR.; ''Identification of Protor as a novel Rictor-binding component of mTOR complex-2.''; PubMed Europe PMC Scholia
  30. Zhang J, Zhang P, Wei Y, Piao HL, Wang W, Maddika S, Wang M, Chen D, Sun Y, Hung MC, Chen J, Ma L.; ''Deubiquitylation and stabilization of PTEN by USP13.''; PubMed Europe PMC Scholia
  31. Masson K, Rönnstrand L.; ''Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3.''; PubMed Europe PMC Scholia
  32. Herbst RS.; ''Review of epidermal growth factor receptor biology.''; PubMed Europe PMC Scholia
  33. Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR.; ''A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types.''; PubMed Europe PMC Scholia
  34. Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, Sartor CI, Rearick WA, McCall W, Sgagias MK, Cowan KH, Earp HS.; ''Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.''; PubMed Europe PMC Scholia
  35. Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L.; ''Cracking the estrogen receptor's posttranslational code in breast tumors.''; PubMed Europe PMC Scholia
  36. Mitchell RM, Janssen MJ, Karavanova I, Vullhorst D, Furth K, Makusky A, Markey SP, Buonanno A.; ''ErbB4 reduces synaptic GABAA currents independent of its receptor tyrosine kinase activity.''; PubMed Europe PMC Scholia
  37. Edling CE, Hallberg B.; ''c-Kit--a hematopoietic cell essential receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  38. Toledo F, Wahl GM.; ''MDM2 and MDM4: p53 regulators as targets in anticancer therapy.''; PubMed Europe PMC Scholia
  39. Rena G, Guo S, Cichy SC, Unterman TG, Cohen P.; ''Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B.''; PubMed Europe PMC Scholia
  40. Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF.; ''Molecular cloning of a new transforming gene from a chemically transformed human cell line.''; PubMed Europe PMC Scholia
  41. Kabuyama Y, Nakatsu N, Homma Y, Fukui Y.; ''Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus.''; PubMed Europe PMC Scholia
  42. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, Henderson JM, Kutok JL, Rajewsky K.; ''Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes.''; PubMed Europe PMC Scholia
  43. Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J.; ''Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.''; PubMed Europe PMC Scholia
  44. Lee JT, Shan J, Zhong J, Li M, Zhou B, Zhou A, Parsons R, Gu W.; ''RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation.''; PubMed Europe PMC Scholia
  45. Zhu Y, Sullivan LL, Nair SS, Williams CC, Pandey AK, Marrero L, Vadlamudi RK, Jones FE.; ''Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells.''; PubMed Europe PMC Scholia
  46. Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S.; ''Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation.''; PubMed Europe PMC Scholia
  47. Li Y, Tsang CK, Wang S, Li XX, Yang Y, Fu L, Huang W, Li M, Wang HY, Zheng XF.; ''MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription.''; PubMed Europe PMC Scholia
  48. Liu P, Cheng H, Roberts TM, Zhao JJ.; ''Targeting the phosphoinositide 3-kinase pathway in cancer.''; PubMed Europe PMC Scholia
  49. Reber L, Da Silva CA, Frossard N.; ''Stem cell factor and its receptor c-Kit as targets for inflammatory diseases.''; PubMed Europe PMC Scholia
  50. del Peso L, González-García M, Page C, Herrera R, Nuñez G.; ''Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.''; PubMed Europe PMC Scholia
  51. Hays JL, Watowich SJ.; ''Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  52. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  53. Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMed Europe PMC Scholia
  54. Burgering BM, Coffer PJ.; ''Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction.''; PubMed Europe PMC Scholia
  55. Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMed Europe PMC Scholia
  56. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C.; ''Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud.''; PubMed Europe PMC Scholia
  57. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMed Europe PMC Scholia
  58. Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, de Belle I.; ''The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling.''; PubMed Europe PMC Scholia
  59. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM.; ''A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.''; PubMed Europe PMC Scholia
  60. Rowley RB, Burkhardt AL, Chao HG, Matsueda GR, Bolen JB.; ''Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation.''; PubMed Europe PMC Scholia
  61. Bradshaw JM.; ''The Src, Syk, and Tec family kinases: distinct types of molecular switches.''; PubMed Europe PMC Scholia
  62. Vasudevan KM, Burikhanov R, Goswami A, Rangnekar VM.; ''Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras.''; PubMed Europe PMC Scholia
  63. Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, Hess D, Hemmings BA.; ''Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation.''; PubMed Europe PMC Scholia
  64. Yuan L, Lv Y, Li H, Gao H, Song S, Zhang Y, Xing G, Kong X, Wang L, Li Y, Zhou T, Gao D, Xiao ZX, Yin Y, Wei W, He F, Zhang L.; ''Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.''; PubMed Europe PMC Scholia
  65. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM.; ''Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.''; PubMed Europe PMC Scholia
  66. Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMed Europe PMC Scholia
  67. Sun M, Hillmann P, Hofmann BT, Hart JR, Vogt PK.; ''Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.''; PubMed Europe PMC Scholia
  68. Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL.; ''Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors.''; PubMed Europe PMC Scholia
  69. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM.; ''Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.''; PubMed Europe PMC Scholia
  70. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G.; ''The E2F1-3 transcription factors are essential for cellular proliferation.''; PubMed Europe PMC Scholia
  71. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMed Europe PMC Scholia
  72. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC.; ''Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.''; PubMed Europe PMC Scholia
  73. Stone JC.; ''Regulation of Ras in lymphocytes: get a GRP.''; PubMed Europe PMC Scholia
  74. Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le Sage C, Agami R, Tuschl T, Holland EC.; ''The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo.''; PubMed Europe PMC Scholia
  75. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMed Europe PMC Scholia
  76. Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, Atfi A, Earp HS.; ''The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation.''; PubMed Europe PMC Scholia
  77. Sampayo RG, Toscani AM, Rubashkin MG, Thi K, Masullo LA, Violi IL, Lakins JN, Cáceres A, Hines WC, Coluccio Leskow F, Stefani FD, Chialvo DR, Bissell MJ, Weaver VM, Simian M.; ''Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells.''; PubMed Europe PMC Scholia
  78. Omerovic J, Santangelo L, Puggioni EM, Marrocco J, Dall'Armi C, Palumbo C, Belleudi F, Di Marcotullio L, Frati L, Torrisi MR, Cesareni G, Gulino A, Alimandi M.; ''The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.''; PubMed Europe PMC Scholia
  79. Lösel R, Wehling M.; ''Nongenomic actions of steroid hormones.''; PubMed Europe PMC Scholia
  80. Borgatti P, Martelli AM, Tabellini G, Bellacosa A, Capitani S, Neri LM.; ''Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin.''; PubMed Europe PMC Scholia
  81. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed Europe PMC Scholia
  82. Ahrens S, Jaramillo S, Yu K, Ghosh S, Hwang GR, Paik R, Lai C, He M, Huang ZJ, Li B.; ''ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection.''; PubMed Europe PMC Scholia
  83. Saouaf SJ, Mahajan S, Rowley RB, Kut SA, Fargnoli J, Burkhardt AL, Tsukada S, Witte ON, Bolen JB.; ''Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement.''; PubMed Europe PMC Scholia
  84. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  85. Clarke JH, Giudici ML, Burke JE, Williams RL, Maloney DJ, Marugan J, Irvine RF.; ''The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site.''; PubMed Europe PMC Scholia
  86. Clarke JH, Emson PC, Irvine RF.; ''Localization of phosphatidylinositol phosphate kinase IIgamma in kidney to a membrane trafficking compartment within specialized cells of the nephron.''; PubMed Europe PMC Scholia
  87. Wu X, Bayle JH, Olson D, Levine AJ.; ''The p53-mdm-2 autoregulatory feedback loop.''; PubMed Europe PMC Scholia
  88. Rodrigues GA, Park M.; ''Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  89. Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMed Europe PMC Scholia
  90. Lee MS, Jeong MH, Lee HW, Han HJ, Ko A, Hewitt SM, Kim JH, Chun KH, Chung JY, Lee C, Cho H, Song J.; ''PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis.''; PubMed Europe PMC Scholia
  91. Clarke JH, Irvine RF.; ''Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization.''; PubMed Europe PMC Scholia
  92. Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M, Hopkins B, Keniry M, Sulis ML, Mense S, Hibshoosh H, Parsons R.; ''Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a.''; PubMed Europe PMC Scholia
  93. Gilmore-Hebert M, Ramabhadran R, Stern DF.; ''Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways.''; PubMed Europe PMC Scholia
  94. Park H, Poo MM.; ''Neurotrophin regulation of neural circuit development and function.''; PubMed Europe PMC Scholia
  95. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G.; ''Targeting MET in cancer: rationale and progress.''; PubMed Europe PMC Scholia
  96. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC Scholia
  97. Scheid MP, Marignani PA, Woodgett JR.; ''Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B.''; PubMed Europe PMC Scholia
  98. Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, Jones J, Andritsos L, Puri KD, Lannutti BJ, Giese NA, Zhang X, Wei L, Byrd JC, Johnson AJ.; ''Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.''; PubMed Europe PMC Scholia
  99. Hata D, Nakamura T, Kawakami T, Kawakami Y, Herren B, Mayumi M.; ''Tyrosine phosphorylation of MB-1, B29, and HS1 proteins in human B cells following receptor crosslinking.''; PubMed Europe PMC Scholia
  100. Halstead JR, van Rheenen J, Snel MH, Meeuws S, Mohammed S, D'Santos CS, Heck AJ, Jalink K, Divecha N.; ''A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis.''; PubMed Europe PMC Scholia
  101. Dailey L, Ambrosetti D, Mansukhani A, Basilico C.; ''Mechanisms underlying differential responses to FGF signaling.''; PubMed Europe PMC Scholia
  102. Veiga E, Cossart P.; ''Listeria hijacks the clathrin-dependent endocytic machinery to invade mammalian cells.''; PubMed Europe PMC Scholia
  103. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed Europe PMC Scholia
  104. Maina F, Panté G, Helmbacher F, Andres R, Porthin A, Davies AM, Ponzetto C, Klein R.; ''Coupling Met to specific pathways results in distinct developmental outcomes.''; PubMed Europe PMC Scholia
  105. Liu Y.; ''Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action.''; PubMed Europe PMC Scholia
  106. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX.; ''Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.''; PubMed Europe PMC Scholia
  107. Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER.; ''A conserved mechanism for steroid receptor translocation to the plasma membrane.''; PubMed Europe PMC Scholia
  108. Yang W, Rozan LM, McDonald ER, Navaraj A, Liu JJ, Matthew EM, Wang W, Dicker DT, El-Deiry WS.; ''CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation.''; PubMed Europe PMC Scholia
  109. Cheng QC, Tikhomirov O, Zhou W, Carpenter G.; ''Ectodomain cleavage of ErbB-4: characterization of the cleavage site and m80 fragment.''; PubMed Europe PMC Scholia
  110. Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J.; ''Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications.''; PubMed Europe PMC Scholia
  111. Inoki K, Li Y, Zhu T, Wu J, Guan KL.; ''TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.''; PubMed Europe PMC Scholia
  112. Chang KY, Tsai SY, Wu CM, Yen CJ, Chuang BF, Chang JY.; ''Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo.''; PubMed Europe PMC Scholia
  113. Komuro A, Nagai M, Navin NE, Sudol M.; ''WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus.''; PubMed Europe PMC Scholia
  114. Hayes NV, Blackburn E, Smart LV, Boyle MM, Russell GA, Frost TM, Morgan BJ, Baines AJ, Gullick WJ.; ''Identification and characterization of novel spliced variants of neuregulin 4 in prostate cancer.''; PubMed Europe PMC Scholia
  115. Oude Weernink PA, López de Jesús M, Schmidt M.; ''Phospholipase D signaling: orchestration by PIP2 and small GTPases.''; PubMed Europe PMC Scholia
  116. Riese DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF.; ''The cellular response to neuregulins is governed by complex interactions of the erbB receptor family.''; PubMed Europe PMC Scholia
  117. Penington DJ, Bryant I, Riese DJ.; ''Constitutively active ErbB4 and ErbB2 mutants exhibit distinct biological activities.''; PubMed Europe PMC Scholia
  118. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  119. Chen SY, Chen HC.; ''Direct interaction of focal adhesion kinase (FAK) with Met is required for FAK to promote hepatocyte growth factor-induced cell invasion.''; PubMed Europe PMC Scholia
  120. Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T, Shimabe M, Nakagawa M, Imai Y, Kitamura T, Kurokawa M.; ''Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins.''; PubMed Europe PMC Scholia
  121. Ni CY, Murphy MP, Golde TE, Carpenter G.; ''gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  122. Jeffrey PD, Gorina S, Pavletich NP.; ''Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms.''; PubMed Europe PMC Scholia
  123. Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y.; ''Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.''; PubMed Europe PMC Scholia
  124. Meng Z, Jia LF, Gan YH.; ''PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition.''; PubMed Europe PMC Scholia
  125. Ferracini R, Longati P, Naldini L, Vigna E, Comoglio PM.; ''Identification of the major autophosphorylation site of the Met/hepatocyte growth factor receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  126. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM.; ''Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.''; PubMed Europe PMC Scholia
  127. Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMed Europe PMC Scholia
  128. Wali VB, Haskins JW, Gilmore-Hebert M, Platt JT, Liu Z, Stern DF.; ''Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells.''; PubMed Europe PMC Scholia
  129. Wang W, Chen Y, Wang S, Hu N, Cao Z, Wang W, Tong T, Zhang X.; ''PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase.''; PubMed Europe PMC Scholia
  130. Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG.; ''Direct identification of PTEN phosphorylation sites.''; PubMed Europe PMC Scholia
  131. Schlessinger J.; ''Common and distinct elements in cellular signaling via EGF and FGF receptors.''; PubMed Europe PMC Scholia
  132. Da Silva-Ferrada E, Xolalpa W, Lang V, Aillet F, Martin-Ruiz I, de la Cruz-Herrera CF, Lopitz-Otsoa F, Carracedo A, Goldenberg SJ, Rivas C, England P, Rodríguez MS.; ''Analysis of SUMOylated proteins using SUMO-traps.''; PubMed Europe PMC Scholia
  133. Bertotti A, Burbridge MF, Gastaldi S, Galimi F, Torti D, Medico E, Giordano S, Corso S, Rolland-Valognes G, Lockhart BP, Hickman JA, Comoglio PM, Trusolino L.; ''Only a subset of Met-activated pathways are required to sustain oncogene addiction.''; PubMed Europe PMC Scholia
  134. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP.; ''Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.''; PubMed Europe PMC Scholia
  135. Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM.; ''The ubiquitin ligase COP1 is a critical negative regulator of p53.''; PubMed Europe PMC Scholia
  136. Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, Ho H, Wang S, Papp E, Bradshaw JM.; ''Molecular mechanism of the Syk activation switch.''; PubMed Europe PMC Scholia
  137. Cobrinik D.; ''Pocket proteins and cell cycle control.''; PubMed Europe PMC Scholia
  138. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed Europe PMC Scholia
  139. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP.; ''The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network.''; PubMed Europe PMC Scholia
  140. van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.''; PubMed Europe PMC Scholia
  141. Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K.; ''Purification and characterization of human Syk produced using a baculovirus expression system.''; PubMed Europe PMC Scholia
  142. Milne D, Kampanis P, Nicol S, Dias S, Campbell DG, Fuller-Pace F, Meek D.; ''A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein.''; PubMed Europe PMC Scholia
  143. Ramel D, Lagarrigue F, Dupuis-Coronas S, Chicanne G, Leslie N, Gaits-Iacovoni F, Payrastre B, Tronchère H.; ''PtdIns5P protects Akt from dephosphorylation through PP2A inhibition.''; PubMed Europe PMC Scholia
  144. Rogalski SL, Appleyard SM, Pattillo A, Terman GW, Chavkin C.; ''TrkB activation by brain-derived neurotrophic factor inhibits the G protein-gated inward rectifier Kir3 by tyrosine phosphorylation of the channel.''; PubMed Europe PMC Scholia
  145. Escrivà M, Peiró S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentís B, Murray SA, Francí C, Gridley T, Virtanen I, García de Herreros A.; ''Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis.''; PubMed Europe PMC Scholia
  146. Niemann HH, Jäger V, Butler PJ, van den Heuvel J, Schmidt S, Ferraris D, Gherardi E, Heinz DW.; ''Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB.''; PubMed Europe PMC Scholia
  147. Khor TO, Gul YA, Ithnin H, Seow HF.; ''Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma.''; PubMed Europe PMC Scholia
  148. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS.; ''Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation.''; PubMed Europe PMC Scholia
  149. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  150. Carter RH, Park DJ, Rhee SG, Fearon DT.; ''Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes.''; PubMed Europe PMC Scholia
  151. Du K, Montminy M.; ''CREB is a regulatory target for the protein kinase Akt/PKB.''; PubMed Europe PMC Scholia
  152. Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMed Europe PMC Scholia
  153. Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M.; ''Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level.''; PubMed Europe PMC Scholia
  154. Loiarro M, Capolunghi F, Fantò N, Gallo G, Campo S, Arseni B, Carsetti R, Carminati P, De Santis R, Ruggiero V, Sette C.; ''Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound.''; PubMed Europe PMC Scholia
  155. Fredriksson L, Li H, Eriksson U.; ''The PDGF family: four gene products form five dimeric isoforms.''; PubMed Europe PMC Scholia
  156. Burke JE, Vadas O, Berndt A, Finegan T, Perisic O, Williams RL.; ''Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α.''; PubMed Europe PMC Scholia
  157. Saldaña-Meyer R, Recillas-Targa F.; ''Transcriptional and epigenetic regulation of the p53 tumor suppressor gene.''; PubMed Europe PMC Scholia
  158. Koh H, Jee K, Lee B, Kim J, Kim D, Yun YH, Kim JW, Choi HS, Chung J.; ''Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt.''; PubMed Europe PMC Scholia
  159. Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, Xu D, Fink LM, Ward DC, Ma Y.; ''SALL4 is a key regulator of survival and apoptosis in human leukemic cells.''; PubMed Europe PMC Scholia
  160. Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMed Europe PMC Scholia
  161. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME.; ''Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.''; PubMed Europe PMC Scholia
  162. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, García-Echeverría C.; ''Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.''; PubMed Europe PMC Scholia
  163. Woo RS, Lee JH, Kim HS, Baek CH, Song DY, Suh YH, Baik TK.; ''Neuregulin-1 protects against neurotoxicities induced by Swedish amyloid precursor protein via the ErbB4 receptor.''; PubMed Europe PMC Scholia
  164. Takagi M, Absalon MJ, McLure KG, Kastan MB.; ''Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.''; PubMed Europe PMC Scholia
  165. Utermark T, Rao T, Cheng H, Wang Q, Lee SH, Wang ZC, Iglehart JD, Roberts TM, Muller WJ, Zhao JJ.; ''The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis.''; PubMed Europe PMC Scholia
  166. Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G.; ''Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain.''; PubMed Europe PMC Scholia
  167. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD, Panayotou G.; ''Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction.''; PubMed Europe PMC Scholia
  168. Shen SM, Guo M, Xiong Z, Yu Y, Zhao XY, Zhang FF, Chen GQ.; ''AIF inhibits tumor metastasis by protecting PTEN from oxidation.''; PubMed Europe PMC Scholia
  169. Lu B, Pang PT, Woo NH.; ''The yin and yang of neurotrophin action.''; PubMed Europe PMC Scholia
  170. Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMed Europe PMC Scholia
  171. Boonyaratanakornkit V.; ''Scaffolding proteins mediating membrane-initiated extra-nuclear actions of estrogen receptor.''; PubMed Europe PMC Scholia
  172. Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ, Sebti SM.; ''The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane.''; PubMed Europe PMC Scholia
  173. Rio C, Buxbaum JD, Peschon JJ, Corfas G.; ''Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4.''; PubMed Europe PMC Scholia
  174. Weidner KM, Sachs M, Riethmacher D, Birchmeier W.; ''Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells.''; PubMed Europe PMC Scholia
  175. Zhang Y, Xiong Y, Yarbrough WG.; ''ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.''; PubMed Europe PMC Scholia
  176. Longati P, Bardelli A, Ponzetto C, Naldini L, Comoglio PM.; ''Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor).''; PubMed Europe PMC Scholia
  177. Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA, Polley MY, Ozawa T, Berger MS, Aftab DT, Prados MD, Haas-Kogan DA.; ''Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide.''; PubMed Europe PMC Scholia
  178. Riese DJ, Komurasaki T, Plowman GD, Stern DF.; ''Activation of ErbB4 by the bifunctional epidermal growth factor family hormone epiregulin is regulated by ErbB2.''; PubMed Europe PMC Scholia
  179. Cohen BD, Green JM, Foy L, Fell HP.; ''HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers.''; PubMed Europe PMC Scholia
  180. Heldin CH, Westermark B.; ''Mechanism of action and in vivo role of platelet-derived growth factor.''; PubMed Europe PMC Scholia
  181. Van Noesel CJ, Brouns GS, van Schijndel GM, Bende RJ, Mason DY, Borst J, van Lier RA.; ''Comparison of human B cell antigen receptor complexes: membrane-expressed forms of immunoglobulin (Ig)M, IgD, and IgG are associated with structurally related heterodimers.''; PubMed Europe PMC Scholia
  182. Borowiak M, Garratt AN, Wüstefeld T, Strehle M, Trautwein C, Birchmeier C.; ''Met provides essential signals for liver regeneration.''; PubMed Europe PMC Scholia
  183. Bibel M, Barde YA.; ''Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system.''; PubMed Europe PMC Scholia
  184. Du K, Herzig S, Kulkarni RN, Montminy M.; ''TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.''; PubMed Europe PMC Scholia
  185. Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C, Birchmeier W.; ''c-Met is essential for wound healing in the skin.''; PubMed Europe PMC Scholia
  186. Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X.; ''NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN.''; PubMed Europe PMC Scholia
  187. Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK.; ''Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.''; PubMed Europe PMC Scholia
  188. Oess S, Icking A, Fulton D, Govers R, Müller-Esterl W.; ''Subcellular targeting and trafficking of nitric oxide synthases.''; PubMed Europe PMC Scholia
  189. Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M, Hemmings BA.; ''Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane.''; PubMed Europe PMC Scholia
  190. Del Pino I, García-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martínez de Lagrán M, Ciceri G, Gabaldón MV, Moratal D, Dierssen M, Canals S, Marín O, Rico B.; ''Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes.''; PubMed Europe PMC Scholia
  191. Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, Lodish HF, Lim B.; ''MicroRNA-125b is a novel negative regulator of p53.''; PubMed Europe PMC Scholia
  192. Verrastro I, Tveen-Jensen K, Woscholski R, Spickett CM, Pitt AR.; ''Reversible oxidation of phosphatase and tensin homolog (PTEN) alters its interactions with signaling and regulatory proteins.''; PubMed Europe PMC Scholia
  193. Amin DN, Perkins AS, Stern DF.; ''Gene expression profiling of ErbB receptor and ligand-dependent transcription.''; PubMed Europe PMC Scholia
  194. Sanchez M, Misulovin Z, Burkhardt AL, Mahajan S, Costa T, Franke R, Bolen JB, Nussenzweig M.; ''Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.''; PubMed Europe PMC Scholia
  195. Skaper SD.; ''The neurotrophin family of neurotrophic factors: an overview.''; PubMed Europe PMC Scholia
  196. Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMed Europe PMC Scholia
  197. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP.; ''A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.''; PubMed Europe PMC Scholia
  198. Trusolino L, Bertotti A, Comoglio PM.; ''MET signalling: principles and functions in development, organ regeneration and cancer.''; PubMed Europe PMC Scholia
  199. Lange CA, Gioeli D, Hammes SR, Marker PC.; ''Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer.''; PubMed Europe PMC Scholia
  200. Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M.; ''Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.''; PubMed Europe PMC Scholia
  201. Carpenter G.; ''Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways.''; PubMed Europe PMC Scholia
  202. Pedram A, Razandi M, Deschenes RJ, Levin ER.; ''DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors.''; PubMed Europe PMC Scholia
  203. Petrini I.; ''Biology of MET: a double life between normal tissue repair and tumor progression.''; PubMed Europe PMC Scholia
  204. Leslie NR, Kriplani N, Hermida MA, Alvarez-Garcia V, Wise HM.; ''The PTEN protein: cellular localization and post-translational regulation.''; PubMed Europe PMC Scholia
  205. Chan PC, Sudhakar JN, Lai CC, Chen HC.; ''Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions.''; PubMed Europe PMC Scholia
  206. Gauld SB, Cambier JC.; ''Src-family kinases in B-cell development and signaling.''; PubMed Europe PMC Scholia
  207. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S.; ''Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase.''; PubMed Europe PMC Scholia
  208. Irish JM, Czerwinski DK, Nolan GP, Levy R.; ''Kinetics of B cell receptor signaling in human B cell subsets mapped by phosphospecific flow cytometry.''; PubMed Europe PMC Scholia
  209. Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M.; ''S-palmitoylation modulates human estrogen receptor-alpha functions.''; PubMed Europe PMC Scholia
  210. Lu J, Jeong HW, Kong N, Yang Y, Carroll J, Luo HR, Silberstein LE, Yupoma, Chai L.; ''Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex.''; PubMed Europe PMC Scholia
  211. Rudd CE.; ''Adaptors and molecular scaffolds in immune cell signaling.''; PubMed Europe PMC Scholia
  212. Elenius K, Paul S, Allison G, Sun J, Klagsbrun M.; ''Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation.''; PubMed Europe PMC Scholia
  213. Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H.; ''Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens.''; PubMed Europe PMC Scholia
  214. Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G, Rameh L, Loda M, Pandolfi PP.; ''Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.''; PubMed Europe PMC Scholia
  215. van Leeuwen JE, Samelson LE.; ''T cell antigen-receptor signal transduction.''; PubMed Europe PMC Scholia
  216. Mori Y, Wakamori M, Miyakawa T, Hermosura M, Hara Y, Nishida M, Hirose K, Mizushima A, Kurosaki M, Mori E, Gotoh K, Okada T, Fleig A, Penner R, Iino M, Kurosaki T.; ''Transient receptor potential 1 regulates capacitative Ca(2+) entry and Ca(2+) release from endoplasmic reticulum in B lymphocytes.''; PubMed Europe PMC Scholia
  217. Nel AE, Landreth GE, Goldschmidt-Clermont PJ, Tung HE, Galbraith RM.; ''Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin.''; PubMed Europe PMC Scholia
  218. Hammes SR, Levin ER.; ''Minireview: Recent advances in extranuclear steroid receptor actions.''; PubMed Europe PMC Scholia
  219. Lu Y, Sun XD, Hou FQ, Bi LL, Yin DM, Liu F, Chen YJ, Bean JC, Jiao HF, Liu X, Li BM, Xiong WC, Gao TM, Mei L.; ''Maintenance of GABAergic activity by neuregulin 1-ErbB4 in amygdala for fear memory.''; PubMed Europe PMC Scholia
  220. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M.; ''Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol.''; PubMed Europe PMC Scholia
  221. Pacher P, Beckman JS, Liaudet L.; ''Nitric oxide and peroxynitrite in health and disease.''; PubMed Europe PMC Scholia
  222. Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, Mak TW, Neel BG, Raught B, Stambolic V.; ''Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress.''; PubMed Europe PMC Scholia
  223. Van Themsche C, Leblanc V, Parent S, Asselin E.; ''X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization.''; PubMed Europe PMC Scholia
  224. Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMed Europe PMC Scholia
  225. Farach-Carson MC, Davis PJ.; ''Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways.''; PubMed Europe PMC Scholia
  226. Paatero I, Jokilammi A, Heikkinen PT, Iljin K, Kallioniemi OP, Jones FE, Jaakkola PM, Elenius K.; ''Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling.''; PubMed Europe PMC Scholia
  227. Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T, Gray N, Zhao J.; ''Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.''; PubMed Europe PMC Scholia
  228. Chittenden T, Livingston DM, Kaelin WG.; ''The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein.''; PubMed Europe PMC Scholia
  229. Fu SM, Winchester RJ, Kunkel HG.; ''Occurrence of surface IgM, IgD, and free light chains of human lymphocytes.''; PubMed Europe PMC Scholia
  230. Schulze WX, Deng L, Mann M.; ''Phosphotyrosine interactome of the ErbB-receptor kinase family.''; PubMed Europe PMC Scholia
  231. Guan YF, Wu CY, Fang YY, Zeng YN, Luo ZY, Li SJ, Li XW, Zhu XH, Mei L, Gao TM.; ''Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission.''; PubMed Europe PMC Scholia
  232. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMed Europe PMC Scholia
  233. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW.; ''Regulation of PTEN transcription by p53.''; PubMed Europe PMC Scholia
  234. Maddika S, Kavela S, Rani N, Palicharla VR, Pokorny JL, Sarkaria JN, Chen J.; ''WWP2 is an E3 ubiquitin ligase for PTEN.''; PubMed Europe PMC Scholia
  235. Tauszig-Delamasure S, Yu LY, Cabrera JR, Bouzas-Rodriguez J, Mermet-Bouvier C, Guix C, Bordeaux MC, Arumäe U, Mehlen P.; ''The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm.''; PubMed Europe PMC Scholia
  236. Jones FE, Welte T, Fu XY, Stern DF.; ''ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation.''; PubMed Europe PMC Scholia
  237. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE.; ''A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.''; PubMed Europe PMC Scholia
  238. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC.; ''HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation.''; PubMed Europe PMC Scholia
  239. Wells A.; ''EGF receptor.''; PubMed Europe PMC Scholia
  240. Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman KG, Farnebo M.; ''Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.''; PubMed Europe PMC Scholia
  241. Schwartz N, Verma A, Bivens CB, Schwartz Z, Boyan BD.; ''Rapid steroid hormone actions via membrane receptors.''; PubMed Europe PMC Scholia
  242. Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM.; ''WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function.''; PubMed Europe PMC Scholia
  243. Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C.; ''Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor.''; PubMed Europe PMC Scholia
  244. Saouaf SJ, Kut SA, Fargnoli J, Rowley RB, Bolen JB, Mahajan S.; ''Reconstitution of the B cell antigen receptor signaling components in COS cells.''; PubMed Europe PMC Scholia
  245. Bokoch GM, Vlahos CJ, Wang Y, Knaus UG, Traynor-Kaplan AE.; ''Rac GTPase interacts specifically with phosphatidylinositol 3-kinase.''; PubMed Europe PMC Scholia
  246. Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N.; ''Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor.''; PubMed Europe PMC Scholia
  247. Shen YH, Zhang L, Gan Y, Wang X, Wang J, LeMaire SA, Coselli JS, Wang XL.; ''Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells.''; PubMed Europe PMC Scholia
  248. González-Santamaría J, Campagna M, Ortega-Molina A, Marcos-Villar L, de la Cruz-Herrera CF, González D, Gallego P, Lopitz-Otsoa F, Esteban M, Rodríguez MS, Serrano M, Rivas C.; ''Regulation of the tumor suppressor PTEN by SUMO.''; PubMed Europe PMC Scholia
  249. Haskins JW, Zhang S, Means RE, Kelleher JK, Cline GW, Canfrán-Duque A, Suárez Y, Stern DF.; ''Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake.''; PubMed Europe PMC Scholia
  250. Rocher G, Letourneux C, Lenormand P, Porteu F.; ''Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity.''; PubMed Europe PMC Scholia
  251. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  252. Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U, Karreth F, Poliseno L, Provero P, Di Cunto F, Lieberman J, Rigoutsos I, Pandolfi PP.; ''Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.''; PubMed Europe PMC Scholia
  253. Murga C, Zohar M, Teramoto H, Gutkind JS.; ''Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB.''; PubMed Europe PMC Scholia
  254. Oude Weernink PA, Schmidt M, Jakobs KH.; ''Regulation and cellular roles of phosphoinositide 5-kinases.''; PubMed Europe PMC Scholia
  255. Le Romancer M, Treilleux I, Leconte N, Robin-Lespinasse Y, Sentis S, Bouchekioua-Bouzaghou K, Goddard S, Gobert-Gosse S, Corbo L.; ''Regulation of estrogen rapid signaling through arginine methylation by PRMT1.''; PubMed Europe PMC Scholia
  256. Okumura K, Mendoza M, Bachoo RM, DePinho RA, Cavenee WK, Furnari FB.; ''PCAF modulates PTEN activity.''; PubMed Europe PMC Scholia
  257. Lemmon MA, Schlessinger J.; ''Cell signaling by receptor tyrosine kinases.''; PubMed Europe PMC Scholia
  258. Landgraf KE, Pilling C, Falke JJ.; ''Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain.''; PubMed Europe PMC Scholia
  259. Chao MV.; ''Neurotrophins and their receptors: a convergence point for many signalling pathways.''; PubMed Europe PMC Scholia
  260. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF.; ''Met, metastasis, motility and more.''; PubMed Europe PMC Scholia
  261. Wade M, Li YC, Wahl GM.; ''MDM2, MDMX and p53 in oncogenesis and cancer therapy.''; PubMed Europe PMC Scholia
  262. Coggeshall KM, McHugh JC, Altman A.; ''Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes.''; PubMed Europe PMC Scholia
  263. Murray DW, Didier S, Chan A, Paulino V, Van Aelst L, Ruggieri R, Tran NL, Byrne AT, Symons M.; ''Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation.''; PubMed Europe PMC Scholia
  264. Helmbacher F, Dessaud E, Arber S, deLapeyrière O, Henderson CE, Klein R, Maina F.; ''Met signaling is required for recruitment of motor neurons to PEA3-positive motor pools.''; PubMed Europe PMC Scholia
  265. Weidner KM, Sachs M, Birchmeier W.; ''The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells.''; PubMed Europe PMC Scholia
  266. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJ, Wan NC, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ.; ''The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .''; PubMed Europe PMC Scholia
  267. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  268. Flaswinkel H, Reth M.; ''Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor.''; PubMed Europe PMC Scholia
  269. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC.; ''Regulation of cell death protease caspase-9 by phosphorylation.''; PubMed Europe PMC Scholia
  270. Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD, Salem HH.; ''PI 3-kinase p110beta: a new target for antithrombotic therapy.''; PubMed Europe PMC Scholia
  271. Rameh LE, Tolias KF, Duckworth BC, Cantley LC.; ''A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.''; PubMed Europe PMC Scholia
  272. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ.; ''Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4.''; PubMed Europe PMC Scholia
  273. Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE.; ''The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone.''; PubMed Europe PMC Scholia
  274. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chène P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, García-Echeverría C, Sellers WR, Voliva CF.; ''Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.''; PubMed Europe PMC Scholia
  275. Kone BC, Kuncewicz T, Zhang W, Yu ZY.; ''Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide.''; PubMed Europe PMC Scholia
  276. Kovacsovics TJ, Bachelot C, Toker A, Vlahos CJ, Duckworth B, Cantley LC, Hartwig JH.; ''Phosphoinositide 3-kinase inhibition spares actin assembly in activating platelets but reverses platelet aggregation.''; PubMed Europe PMC Scholia
  277. Law CL, Sidorenko SP, Chandran KA, Draves KE, Chan AC, Weiss A, Edelhoff S, Disteche CM, Clark EA.; ''Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex.''; PubMed Europe PMC Scholia
  278. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B.; ''Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.''; PubMed Europe PMC Scholia
  279. Torres J, Pulido R.; ''The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation.''; PubMed Europe PMC Scholia
  280. Shinohara H, Kurosaki T.; ''Comprehending the complex connection between PKCbeta, TAK1, and IKK in BCR signaling.''; PubMed Europe PMC Scholia
  281. Lamorte L, Royal I, Naujokas M, Park M.; ''Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions.''; PubMed Europe PMC Scholia
  282. Li N, Zhang Y, Han X, Liang K, Wang J, Feng L, Wang W, Songyang Z, Lin C, Yang L, Yu Y, Chen J.; ''Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth.''; PubMed Europe PMC Scholia
  283. Ikenoue T, Inoki K, Zhao B, Guan KL.; ''PTEN acetylation modulates its interaction with PDZ domain.''; PubMed Europe PMC Scholia
  284. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  285. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C.; ''Scatter factor/hepatocyte growth factor is essential for liver development.''; PubMed Europe PMC Scholia
  286. Hammes SR, Levin ER.; ''Extranuclear steroid receptors: nature and actions.''; PubMed Europe PMC Scholia
  287. Zhang X, Loijens JC, Boronenkov IV, Parker GJ, Norris FA, Chen J, Thum O, Prestwich GD, Majerus PW, Anderson RA.; ''Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules.''; PubMed Europe PMC Scholia
  288. Marlin MC, Li G.; ''Biogenesis and function of the NGF/TrkA signaling endosome.''; PubMed Europe PMC Scholia
  289. Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, Cheng JQ.; ''MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN.''; PubMed Europe PMC Scholia
  290. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB.; ''NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.''; PubMed Europe PMC Scholia
  291. Tan PL, Shavlakadze T, Grounds MD, Arthur PG.; ''Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle.''; PubMed Europe PMC Scholia
  292. Ahmed SF, Deb S, Paul I, Chatterjee A, Mandal T, Chatterjee U, Ghosh MK.; ''The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation.''; PubMed Europe PMC Scholia
  293. Biswas DK, Singh S, Shi Q, Pardee AB, Iglehart JD.; ''Crossroads of estrogen receptor and NF-kappaB signaling.''; PubMed Europe PMC Scholia
  294. Arasada RR, Carpenter G.; ''Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment.''; PubMed Europe PMC Scholia
  295. Lennartsson J, Rönnstrand L.; ''The stem cell factor receptor/c-Kit as a drug target in cancer.''; PubMed Europe PMC Scholia
  296. Marino M, Ascenzi P, Acconcia F.; ''S-palmitoylation modulates estrogen receptor alpha localization and functions.''; PubMed Europe PMC Scholia
  297. La Rosa P, Pesiri V, Leclercq G, Marino M, Acconcia F.; ''Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity.''; PubMed Europe PMC Scholia
  298. Gao T, Furnari F, Newton AC.; ''PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth.''; PubMed Europe PMC Scholia
  299. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, Xu LH, Zhang X, Liu WL, Li MZ, Zhang L, Kang TB, Fu LW, Huang WL, Xia YF, Tsao SW, Li M, Band V, Band H, Shi QH, Zeng YX, Zeng MS.; ''The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells.''; PubMed Europe PMC Scholia
  300. Zeng F, Xu J, Harris RC.; ''Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.''; PubMed Europe PMC Scholia
  301. Crosier PS, Ricciardi ST, Hall LR, Vitas MR, Clark SC, Crosier KE.; ''Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia.''; PubMed Europe PMC Scholia
  302. Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi SG, Kim HJ, Misteli T, Jiang X, Pandolfi PP.; ''Ubiquitination regulates PTEN nuclear import and tumor suppression.''; PubMed Europe PMC Scholia
  303. Schaeper U, Gehring NH, Fuchs KP, Sachs M, Kempkes B, Birchmeier W.; ''Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses.''; PubMed Europe PMC Scholia
  304. Shenoy SS, Nanda H, Lösche M.; ''Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail.''; PubMed Europe PMC Scholia
  305. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMed Europe PMC Scholia
  306. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC.; ''Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.''; PubMed Europe PMC Scholia
  307. Slavik JM, Hutchcroft JE, Bierer BE.; ''CD28/CTLA-4 and CD80/CD86 families: signaling and function.''; PubMed Europe PMC Scholia
  308. Das S, Dixon JE, Cho W.; ''Membrane-binding and activation mechanism of PTEN.''; PubMed Europe PMC Scholia
  309. Uygur B, Abramo K, Leikina E, Vary C, Liaw L, Wu WS.; ''SLUG is a direct transcriptional repressor of PTEN tumor suppressor.''; PubMed Europe PMC Scholia
  310. Sweeney C, Lai C, Riese DJ, Diamonti AJ, Cantley LC, Carraway KL.; ''Ligand discrimination in signaling through an ErbB4 receptor homodimer.''; PubMed Europe PMC Scholia
  311. Letourneux C, Rocher G, Porteu F.; ''B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK.''; PubMed Europe PMC Scholia
  312. Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, Haber DA.; ''Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752.''; PubMed Europe PMC Scholia
  313. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMed Europe PMC Scholia
  314. Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, Thorgeirsson SS.; ''Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair.''; PubMed Europe PMC Scholia
  315. Poo MM.; ''Neurotrophins as synaptic modulators.''; PubMed Europe PMC Scholia
  316. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.''; PubMed Europe PMC Scholia
  317. Rudd CE, Schneider H.; ''Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.''; PubMed Europe PMC Scholia
  318. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T.; ''MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer.''; PubMed Europe PMC Scholia
  319. Kim H, Huang W, Jiang X, Pennicooke B, Park PJ, Johnson MD.; ''Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship.''; PubMed Europe PMC Scholia
  320. Brezski RJ, Monroe JG.; ''B-cell receptor.''; PubMed Europe PMC Scholia
  321. Lang V, Aillet F, Da Silva-Ferrada E, Xolalpa W, Zabaleta L, Rivas C, Rodriguez MS.; ''Analysis of PTEN ubiquitylation and SUMOylation using molecular traps.''; PubMed Europe PMC Scholia
  322. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH.; ''PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling.''; PubMed Europe PMC Scholia
  323. Rönnstrand L.; ''Signal transduction via the stem cell factor receptor/c-Kit.''; PubMed Europe PMC Scholia
  324. Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMed Europe PMC Scholia
  325. Eswarakumar VP, Lax I, Schlessinger J.; ''Cellular signaling by fibroblast growth factor receptors.''; PubMed Europe PMC Scholia
  326. Maehama T, Dixon JE.; ''The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.''; PubMed Europe PMC Scholia
  327. Kaushansky A, Gordus A, Budnik BA, Lane WS, Rush J, MacBeath G.; ''System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties.''; PubMed Europe PMC Scholia
  328. Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMed Europe PMC Scholia
  329. Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K.; ''Association of B cell antigen receptor with protein tyrosine kinase Lyn.''; PubMed Europe PMC Scholia
  330. Acuto O, Michel F.; ''CD28-mediated co-stimulation: a quantitative support for TCR signalling.''; PubMed Europe PMC Scholia
  331. Naldini L, Vigna E, Narsimhan RP, Gaudino G, Zarnegar R, Michalopoulos GK, Comoglio PM.; ''Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET.''; PubMed Europe PMC Scholia
  332. Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM.; ''A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.''; PubMed Europe PMC Scholia
  333. Di Paolo G, Pellegrini L, Letinic K, Cestra G, Zoncu R, Voronov S, Chang S, Guo J, Wenk MR, De Camilli P.; ''Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin.''; PubMed Europe PMC Scholia
  334. Hou XJ, Ni KM, Yang JM, Li XM.; ''Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses.''; PubMed Europe PMC Scholia
  335. Ornitz DM, Marie PJ.; ''FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.''; PubMed Europe PMC Scholia
  336. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  337. Besser D, Bardelli A, Didichenko S, Thelen M, Comoglio PM, Ponzetto C, Nagamine Y.; ''Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2.''; PubMed Europe PMC Scholia
  338. Maina F, Hilton MC, Ponzetto C, Davies AM, Klein R.; ''Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons.''; PubMed Europe PMC Scholia
  339. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC Scholia
  340. Hodakoski C, Hopkins BD, Barrows D, Mense SM, Keniry M, Anderson KE, Kern PA, Hawkins PT, Stephens LR, Parsons R.; ''Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.''; PubMed Europe PMC Scholia
  341. Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA.; ''Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.''; PubMed Europe PMC Scholia
  342. Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG.; ''The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein.''; PubMed Europe PMC Scholia
  343. Lessmann V, Gottmann K, Malcangio M.; ''Neurotrophin secretion: current facts and future prospects.''; PubMed Europe PMC Scholia
  344. Minichiello L.; ''TrkB signalling pathways in LTP and learning.''; PubMed Europe PMC Scholia
  345. Alegre ML, Frauwirth KA, Thompson CB.; ''T-cell regulation by CD28 and CTLA-4.''; PubMed Europe PMC Scholia
  346. Hazan R, Margolis B, Dombalagian M, Ullrich A, Zilberstein A, Schlessinger J.; ''Identification of autophosphorylation sites of HER2/neu.''; PubMed Europe PMC Scholia
  347. Geng F, Zhang J, Wu JL, Zou WJ, Liang ZP, Bi LL, Liu JH, Kong Y, Huang CQ, Li XW, Yang JM, Gao TM.; ''Neuregulin 1-ErbB4 signaling in the bed nucleus of the stria terminalis regulates anxiety-like behavior.''; PubMed Europe PMC Scholia
  348. Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D.; ''ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms.''; PubMed Europe PMC Scholia
  349. Collaud S, Tischler V, Atanassoff A, Wiedl T, Komminoth P, Oehlschlegel C, Weder W, Soltermann A.; ''Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN.''; PubMed Europe PMC Scholia
  350. Williams EJ, Furness J, Walsh FS, Doherty P.; ''Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.''; PubMed Europe PMC Scholia
  351. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMed Europe PMC Scholia
  352. Sun Y, Ikrar T, Davis MF, Gong N, Zheng X, Luo ZD, Lai C, Mei L, Holmes TC, Gandhi SP, Xu X.; ''Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity.''; PubMed Europe PMC Scholia
  353. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  354. Zhang CL, Zou Y, Yu RT, Gage FH, Evans RM.; ''Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.''; PubMed Europe PMC Scholia
  355. Tay Y, Rinn J, Pandolfi PP.; ''The multilayered complexity of ceRNA crosstalk and competition.''; PubMed Europe PMC Scholia
  356. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C.; ''Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation.''; PubMed Europe PMC Scholia
  357. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC Scholia
  358. Li Z, Mei Y, Liu X, Zhou M.; ''Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners.''; PubMed Europe PMC Scholia
  359. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH.; ''Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN.''; PubMed Europe PMC Scholia
  360. Clarke JH, Wang M, Irvine RF.; ''Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases.''; PubMed Europe PMC Scholia
  361. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C.; ''Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases.''; PubMed Europe PMC Scholia
  362. Sakkab D, Lewitzky M, Posern G, Schaeper U, Sachs M, Birchmeier W, Feller SM.; ''Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL.''; PubMed Europe PMC Scholia
  363. Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM.; ''A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family.''; PubMed Europe PMC Scholia
  364. Ichim G, Genevois AL, Ménard M, Yu LY, Coelho-Aguiar JM, Llambi F, Jarrosson-Wuilleme L, Lefebvre J, Tulasne D, Dupin E, Le Douarin N, Arumäe U, Tauszig-Delamasure S, Mehlen P.; ''The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment.''; PubMed Europe PMC Scholia
  365. Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA.; ''Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling.''; PubMed Europe PMC Scholia
  366. Harwood NE, Batista FD.; ''Early events in B cell activation.''; PubMed Europe PMC Scholia
  367. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK.; ''The lipid phosphatase activity of PTEN is critical for its tumor supressor function.''; PubMed Europe PMC Scholia
  368. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  369. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM.; ''Akt phosphorylates and regulates the orphan nuclear receptor Nur77.''; PubMed Europe PMC Scholia
  370. Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS.; ''Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation.''; PubMed Europe PMC Scholia
  371. Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE.; ''The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.''; PubMed Europe PMC Scholia
  372. Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM.; ''Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis.''; PubMed Europe PMC Scholia
  373. Shen K, Novak RF.; ''DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells.''; PubMed Europe PMC Scholia
  374. Palamidessi A, Frittoli E, Garré M, Faretta M, Mione M, Testa I, Diaspro A, Lanzetti L, Scita G, Di Fiore PP.; ''Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration.''; PubMed Europe PMC Scholia
  375. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J.; ''NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations.''; PubMed Europe PMC Scholia
  376. Mayo LD, Donner DB.; ''A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.''; PubMed Europe PMC Scholia
  377. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114764view16:25, 25 January 2021ReactomeTeamReactome version 75
113208view11:27, 2 November 2020ReactomeTeamReactome version 74
112432view15:37, 9 October 2020ReactomeTeamReactome version 73
101336view11:22, 1 November 2018ReactomeTeamreactome version 66
100874view20:56, 31 October 2018ReactomeTeamreactome version 65
100415view19:30, 31 October 2018ReactomeTeamreactome version 64
99964view16:14, 31 October 2018ReactomeTeamreactome version 63
99519view14:47, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99161view12:41, 31 October 2018ReactomeTeamreactome version 62
93830view13:39, 16 August 2017ReactomeTeamreactome version 61
93382view11:22, 9 August 2017ReactomeTeamreactome version 61
88094view09:28, 26 July 2016RyanmillerOntology Term : 'kinase mediated signaling pathway' added !
88093view09:25, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86468view09:18, 11 July 2016ReactomeTeamreactome version 56
83247view10:30, 18 November 2015ReactomeTeamVersion54
81352view12:52, 21 August 2015ReactomeTeamVersion53
76821view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76525view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75858view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75558view10:35, 10 June 2014ReactomeTeamReactome 48 Update
74913view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74557view08:35, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT R-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
AKT inhibitors:AKTComplexR-HSA-2400006 (Reactome)
AKT inhibitorsComplexR-ALL-2399923 (Reactome)
AKT/AKT1 E17K mutantComplexR-HSA-2400013 (Reactome)
AKT1 E17K mutant:PIP2ComplexR-HSA-2219527 (Reactome)
AKT1 E17K ProteinP31749 (Uniprot-TrEMBL)
AKT1 E17KProteinP31749 (Uniprot-TrEMBL)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT1ProteinP31749 (Uniprot-TrEMBL)
AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
AKT2 ProteinP31751 (Uniprot-TrEMBL)
AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
AKT:PIP3:THEM4/TRIB3ComplexR-HSA-199453 (Reactome)
AKT:PIP3ComplexR-HSA-2317329 (Reactome)
AKTComplexR-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated SRC,LCK,EGFR,INSRComplexR-HSA-8857936 (Reactome)
Activated FGFR2b homodimer bound to FGF R-HSA-192606 (Reactome)
Activated FGFR2c homodimer bound to FGF R-HSA-192616 (Reactome)
Activator:PI3K R-HSA-2316432 (Reactome)
Activator:PI3KComplexR-HSA-2316432 (Reactome)
Active AKTComplexR-HSA-202072 (Reactome)
Active AKTComplexR-HSA-202074 (Reactome)
BADProteinQ92934 (Uniprot-TrEMBL)
BEZ235 MetaboliteCHEBI:71952 (ChEBI)
BGT226 MetaboliteCHEBI:71953 (ChEBI)
BKM120 MetaboliteCHEBI:71954 (ChEBI)
CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
CD80 ProteinP33681 (Uniprot-TrEMBL)
CD86 ProteinP42081 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A/BComplexR-HSA-198625 (Reactome)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CHUKProteinO15111 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Costimulation by the CD28 familyPathwayR-HSA-388841 (Reactome) Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation.
The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity.
The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules.
EGF ProteinP01133 (Uniprot-TrEMBL)
EGF-like ligands R-HSA-1233230 (Reactome)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C2 ProteinQ9UKV8 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
FGF1 ProteinP05230 (Uniprot-TrEMBL)
FGF10 ProteinO15520 (Uniprot-TrEMBL)
FGF16 ProteinO43320 (Uniprot-TrEMBL)
FGF17-1 ProteinO60258-1 (Uniprot-TrEMBL)
FGF18 ProteinO76093 (Uniprot-TrEMBL)
FGF19 ProteinO95750 (Uniprot-TrEMBL)
FGF2(10-155) ProteinP09038 (Uniprot-TrEMBL)
FGF20 ProteinQ9NP95 (Uniprot-TrEMBL)
FGF22 ProteinQ9HCT0 (Uniprot-TrEMBL)
FGF23(25-251) ProteinQ9GZV9 (Uniprot-TrEMBL)
FGF3 ProteinP11487 (Uniprot-TrEMBL)
FGF4 ProteinP08620 (Uniprot-TrEMBL)
FGF5-1 ProteinP12034-1 (Uniprot-TrEMBL)
FGF6 ProteinP10767 (Uniprot-TrEMBL)
FGF8-1 ProteinP55075-1 (Uniprot-TrEMBL)
FGF9 ProteinP31371 (Uniprot-TrEMBL)
FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
FOXO1,FOXO3,FOXO4ComplexR-HSA-199272 (Reactome)
FOXO3 ProteinO43524 (Uniprot-TrEMBL)
FOXO4-1 ProteinP98177-1 (Uniprot-TrEMBL)
FOXO4-2 ProteinP98177-2 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GDC0941 MetaboliteCHEBI:65326 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GSK1059615 MetaboliteCHEBI:71955 (ChEBI)
GSK3A ProteinP49840 (Uniprot-TrEMBL)
GSK3B ProteinP49841 (Uniprot-TrEMBL)
GSK3ComplexR-HSA-198358 (Reactome)
GalNAc-T178-FGF23(25-251) ProteinQ9GZV9 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HS MetaboliteCHEBI:28815 (ChEBI)
IER3 ProteinP46695 (Uniprot-TrEMBL)
IER3ProteinP46695 (Uniprot-TrEMBL)
INSR(28-758) ProteinP06213 (Uniprot-TrEMBL)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

KITLG-1(26-190) ProteinP21583-1 (Uniprot-TrEMBL)
KL-1 ProteinQ9UEF7-1 (Uniprot-TrEMBL)
KL-2 ProteinQ9UEF7-2 (Uniprot-TrEMBL)
KLB ProteinQ86Z14 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LY294002 MetaboliteCHEBI:65329 (ChEBI)
MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MK2206 MetaboliteCHEBI:716367 (ChEBI)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NR4A1ProteinP22736 (Uniprot-TrEMBL)
NRG1 R-HSA-1233225 (Reactome)
NRG2 ProteinO14511 (Uniprot-TrEMBL)
Neuregulins R-HSA-1227957 (Reactome)
PDGFA-1 ProteinP04085-1 (Uniprot-TrEMBL)
PDGFA-2 ProteinP04085-2 (Uniprot-TrEMBL)
PDGFB ProteinP01127 (Uniprot-TrEMBL)
PDGFB(82-241) ProteinP01127 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP2ComplexR-HSA-2219520 (Reactome)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2ComplexR-HSA-2243941 (Reactome)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PHLPP (Mn2+ cofactor)ComplexR-HSA-199450 (Reactome)
PHLPP1 ProteinO60346 (Uniprot-TrEMBL)
PHLPP2 ProteinQ6ZVD8 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K mutants,Activator:PI3KComplexR-HSA-2400011 (Reactome)
PI3K Inhibitors:PI3KComplexR-HSA-2400008 (Reactome)
PI3K inhibitorsComplexR-ALL-2399811 (Reactome) PI3K inhibitors bind the catalytic subunit of PIK3CA, blocking its phosphoinositide kinase activity.
PI3K mutants R-HSA-2394006 (Reactome)
PI4PMetaboliteCHEBI:17526 (ChEBI)
PI5PMetaboliteCHEBI:16500 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIP4K2 dimersComplexR-HSA-1806229 (Reactome)
PIP4K2A ProteinP48426 (Uniprot-TrEMBL)
PIP4K2B ProteinP78356 (Uniprot-TrEMBL)
PIP4K2C ProteinQ8TBX8 (Uniprot-TrEMBL)
PIP5K1A ProteinQ99755 (Uniprot-TrEMBL)
PIP5K1A-CComplexR-HSA-1806157 (Reactome)
PIP5K1B ProteinO14986 (Uniprot-TrEMBL)
PIP5K1C ProteinO60331 (Uniprot-TrEMBL)
PP2A-A:PP2A-CComplexR-HSA-6811485 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersComplexR-HSA-6811477 (Reactome)
PP2A-B56-beta,gammaComplexR-HSA-6811526 (Reactome)
PP2AComplexR-HSA-196206 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5A ProteinQ15172 (Uniprot-TrEMBL)
PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP2R5E ProteinQ16537 (Uniprot-TrEMBL)
PRR5 ProteinP85299 (Uniprot-TrEMBL)
PTEN Gene ProteinENSG00000171862 (Ensembl)
PTEN GeneGeneProductENSG00000171862 (Ensembl)
PTEN ProteinP60484 (Uniprot-TrEMBL)
PTEN mRNA ProteinENST00000371953 (Ensembl)
PTEN mRNA:miR-26A RISCComplexR-HSA-2318750 (Reactome)
PTEN mRNARnaENST00000371953 (Ensembl)
PTEN:Mg2+ComplexR-HSA-199426 (Reactome)
PX-866 MetaboliteCHEBI:65345 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
Signaling by EGFRPathwayR-HSA-177929 (Reactome) The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011.
Signaling by ERBB2PathwayR-HSA-1227986 (Reactome) ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).

ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example.

In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.

In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1.

In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.
Signaling by ERBB4PathwayR-HSA-1236394 (Reactome) ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR i.e. HER1), ERBB2 (HER2 i.e. NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed).

ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation, but their downstream signaling and physiological significance have not been studied.


All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).

The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).

Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006). Activation of ERBB4 in breast cancer cell lines leads to JNK-dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka-Cook et al. 2006).

WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).
Signaling by FGFRPathwayR-HSA-190236 (Reactome) The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.

Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.

This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
Signaling by PDGFPathwayR-HSA-186797 (Reactome) Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell.
Signaling by SCF-KITPathwayR-HSA-1433557 (Reactome) Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours.
Signaling by the B Cell Receptor (BCR)PathwayR-HSA-983705 (Reactome) Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesel et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010).
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.
Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006).
Signalling by NGFPathwayR-HSA-166520 (Reactome) Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread.


Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling.
THEM4 ProteinQ5T1C6 (Uniprot-TrEMBL)
THEM4/TRIB3ComplexR-HSA-2400007 (Reactome)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TORC2 complexComplexR-HSA-198626 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Regulates Metabolic GenesPathwayR-HSA-5628897 (Reactome) While the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.

TP53 stimulates transcription of TIGAR, a D-fructose 2,6-bisphosphatase. TIGAR activity decreases glycolytic rate and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006). TP53 may also negatively regulate the rate of glycolysis by inhibiting the expression of glucose transporters GLUT1, GLUT3 and GLUT4 (Kondoh et al. 2005, Schwartzenberg-Bar-Yoseph et al. 2004, Kawauchi et al. 2008).

TP53 negatively regulates several key points in PI3K/AKT signaling and downstream mTOR signaling, decreasing the rate of protein synthesis and, hence, cellular growth. TP53 directly stimulates transcription of the tumor suppressor PTEN, which acts to inhibit PI3K-mediated activation of AKT (Stambolic et al. 2001). TP53 stimulates transcription of sestrin genes, SESN1, SESN2, and SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007). One of sestrin functions may be to reduce and reactivate overoxidized peroxiredoxin PRDX1, thereby reducing ROS levels (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009). Another function of sestrins is to bind the activated AMPK complex and protect it from AKT-mediated inactivation. By enhancing AMPK activity, sestrins negatively regulate mTOR signaling (Budanov and Karin 2008, Cam et al. 2014). The expression of DDIT4 (REDD1), another negative regulator of mTOR signaling, is directly stimulated by TP63 and TP53. DDIT4 prevents AKT-mediated inactivation of TSC1:TSC2 complex, thus inhibiting mTOR cascade (Cam et al. 2014, Ellisen et al. 2002, DeYoung et al. 2008). TP53 may also be involved, directly or indirectly, in regulation of expression of other participants of PI3K/AKT/mTOR signaling, such as PIK3CA (Singh et al. 2002), TSC2 and AMPKB (Feng et al. 2007).

TP53 regulates mitochondrial metabolism through several routes. TP53 stimulates transcription of SCO2 gene, which encodes a mitochondrial cytochrome c oxidase assembly protein (Matoba et al. 2006). TP53 stimulates transcription of RRM2B gene, which encodes a subunit of the ribonucleotide reductase complex, responsible for the conversion of ribonucleotides to deoxyribonucleotides and essential for the maintenance of mitochondrial DNA content in the cell (Tanaka et al. 2000, Bourdon et al. 2007, Kulawiec et al. 2009). TP53 also transactivates mitochondrial transcription factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance (Park et al. 2009). Finally, TP53 stimulates transcription of the mitochondrial glutaminase GLS2, leading to increased mitochondrial respiration rate and reduced ROS levels (Hu et al. 2010).

The great majority of tumor cells generate energy through aerobic glycolysis, rather than the much more efficient aerobic mitochondrial respiration, and this metabolic change is known as the Warburg effect (Warburg 1956). Since the majority of tumor cells have impaired TP53 function, and TP53 regulates a number of genes involved in glycolysis and mitochondrial respiration, it is likely that TP53 inactivation plays an important role in the metabolic derangement of cancer cells such as the Warburg effect and the concomitant increased tumorigenicity (reviewed by Feng and Levine 2010). On the other hand, some mutations of TP53 in Li-Fraumeni syndrome may result in the retention of its wild-type metabolic activities while losing cell cycle and apoptosis functions (Wang et al. 2013). Consistent with such human data, some mutations of p53, unlike p53 null state, retain the ability to regulate energy metabolism while being inactive in regulating its classic gene targets involved in cell cycle, apoptosis and senescence. Retention of metabolic and antioxidant functions of p53 protects p53 mutant mice from early onset tumorigenesis (Li et al. 2012).

TP53 Tetramer:PTEN GeneComplexR-HSA-5632941 (Reactome)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
Triciribine MetaboliteCHEBI:65310 (ChEBI)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
XL147 MetaboliteCHEBI:71957 (ChEBI)
XL765 MetaboliteCHEBI:71958 (ChEBI)
miR-26A RISCComplexR-HSA-2318737 (Reactome)
miR-26A1 ProteinMI0000083 (miRBase mature sequence)
miR-26A2 ProteinMI0000750 (miRBase mature sequence)
p-10Y-ERBB3-1 ProteinP21860-1 (Uniprot-TrEMBL)
p-11Y-PDGFRA ProteinP16234 (Uniprot-TrEMBL)
p-12Y-PDGFRB ProteinP09619 (Uniprot-TrEMBL)
p-5Y-FGFR4 ProteinP22455 (Uniprot-TrEMBL)
p-6Y-CD19 ProteinP15391 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-6Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-6Y-FGFR3b ProteinP22607-2 (Uniprot-TrEMBL)
p-6Y-FGFR3c ProteinP22607-1 (Uniprot-TrEMBL)
p-6Y-FRS2 ProteinQ8WU20 (Uniprot-TrEMBL)
p-6Y-INSR(763-1382) ProteinP06213 (Uniprot-TrEMBL)
p-7Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-7Y-KIT ProteinP10721 (Uniprot-TrEMBL)
p-8Y-FGFR1b ProteinP11362-19 (Uniprot-TrEMBL) While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
p-8Y-FGFR1c ProteinP11362-1 (Uniprot-TrEMBL)
p-FOXO1,p-FOXO3,p-FOXO4ComplexR-HSA-199269 (Reactome)
p-S-AKT:PDPK1:PIP3ComplexR-HSA-2317313 (Reactome)
p-S-AKT:PIP3ComplexR-HSA-2317310 (Reactome)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S15,S356-RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
p-S166,S188-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S183,T246-AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
p-S196-CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
p-S197,S262,T32-FOXO4 ProteinP98177-1 (Uniprot-TrEMBL)
p-S21-GSK3A ProteinP49840 (Uniprot-TrEMBL)
p-S337-PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
p-S351-NR4A1ProteinP22736 (Uniprot-TrEMBL)
p-S368-PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
p-S368-PPP2R5B,p-S337-PPP2R5CComplexR-HSA-6811475 (Reactome)
p-S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-S473-AKT1 E17K mutant:PIP2ComplexR-HSA-2243943 (Reactome)
p-S473-AKT1 E17K ProteinP31749 (Uniprot-TrEMBL)
p-S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-S9-GSK3B ProteinP49841 (Uniprot-TrEMBL)
p-S9/21-GSK3ComplexR-HSA-198373 (Reactome)
p-S939,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-S99-BADProteinQ92934 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-1268261 (Reactome)
p-T-AKTComplexR-HSA-202084 (Reactome)
p-T-CDKN1A/BComplexR-HSA-198605 (Reactome)
p-T145-CDKN1A ProteinP38936 (Uniprot-TrEMBL)
p-T157-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T23-CHUKProteinO15111 (Uniprot-TrEMBL)
p-T24,S256,S319-FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T305-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 E17KProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)
p-T308-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T309-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T32,S142,S207-FOXO4-2 ProteinP98177-2 (Uniprot-TrEMBL)
p-T32,S253,S315-FOXO3 ProteinO43524 (Uniprot-TrEMBL)
p-Y,Y877-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform ProteinQ15303-2 (Uniprot-TrEMBL)
p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform ProteinQ15303-1 (Uniprot-TrEMBL)
p-Y191-CD28 ProteinP10747 (Uniprot-TrEMBL)
p-Y307-PP2AComplexR-HSA-8857938 (Reactome)
p-Y307-PPP2CA ProteinP67775 (Uniprot-TrEMBL)
p-Y307-PPP2CB ProteinP62714 (Uniprot-TrEMBL)
p-Y394-LCK ProteinP06239 (Uniprot-TrEMBL)
p-Y419-SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
p-Y63,Y79,Y110-TRAT1 ProteinQ6PIZ9 (Uniprot-TrEMBL)
perifosine MetaboliteCHEBI:428891 (ChEBI)
wortmannin MetaboliteCHEBI:52289 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-1675776 (Reactome)
ADPArrowR-HSA-1676082 (Reactome)
ADPArrowR-HSA-198270 (Reactome)
ADPArrowR-HSA-198347 (Reactome)
ADPArrowR-HSA-198371 (Reactome)
ADPArrowR-HSA-198599 (Reactome)
ADPArrowR-HSA-198609 (Reactome)
ADPArrowR-HSA-198611 (Reactome)
ADPArrowR-HSA-198613 (Reactome)
ADPArrowR-HSA-198621 (Reactome)
ADPArrowR-HSA-198640 (Reactome)
ADPArrowR-HSA-199298 (Reactome)
ADPArrowR-HSA-199299 (Reactome)
ADPArrowR-HSA-199839 (Reactome)
ADPArrowR-HSA-199863 (Reactome)
ADPArrowR-HSA-200143 (Reactome)
ADPArrowR-HSA-2243938 (Reactome)
ADPArrowR-HSA-2243942 (Reactome)
ADPArrowR-HSA-2316434 (Reactome)
ADPArrowR-HSA-6811454 (Reactome)
ADPArrowR-HSA-8857925 (Reactome)
AKT inhibitors:AKTArrowR-HSA-2400010 (Reactome)
AKT inhibitorsR-HSA-2400010 (Reactome)
AKT/AKT1 E17K mutantR-HSA-2400010 (Reactome)
AKT1 E17K mutant:PIP2ArrowR-HSA-2219536 (Reactome)
AKT1 E17K mutant:PIP2R-HSA-2243938 (Reactome)
AKT1 E17KR-HSA-2219536 (Reactome)
AKT1ArrowR-HSA-6811504 (Reactome)
AKT1S1R-HSA-200143 (Reactome)
AKT:PIP3:THEM4/TRIB3ArrowR-HSA-199443 (Reactome)
AKT:PIP3:THEM4/TRIB3TBarR-HSA-198640 (Reactome)
AKT:PIP3ArrowR-HSA-2317332 (Reactome)
AKT:PIP3R-HSA-198640 (Reactome)
AKT:PIP3R-HSA-199443 (Reactome)
AKTR-HSA-2317332 (Reactome)
ATPR-HSA-1675776 (Reactome)
ATPR-HSA-1676082 (Reactome)
ATPR-HSA-198270 (Reactome)
ATPR-HSA-198347 (Reactome)
ATPR-HSA-198371 (Reactome)
ATPR-HSA-198599 (Reactome)
ATPR-HSA-198609 (Reactome)
ATPR-HSA-198611 (Reactome)
ATPR-HSA-198613 (Reactome)
ATPR-HSA-198621 (Reactome)
ATPR-HSA-198640 (Reactome)
ATPR-HSA-199298 (Reactome)
ATPR-HSA-199299 (Reactome)
ATPR-HSA-199839 (Reactome)
ATPR-HSA-199863 (Reactome)
ATPR-HSA-200143 (Reactome)
ATPR-HSA-2243938 (Reactome)
ATPR-HSA-2243942 (Reactome)
ATPR-HSA-2316434 (Reactome)
ATPR-HSA-6811454 (Reactome)
ATPR-HSA-8857925 (Reactome)
Activated SRC,LCK,EGFR,INSRmim-catalysisR-HSA-8857925 (Reactome)
Activator:PI3Kmim-catalysisR-HSA-2316434 (Reactome)
Active AKTArrowR-HSA-198270 (Reactome)
Active AKTArrowR-HSA-198298 (Reactome)
Active AKTR-HSA-198298 (Reactome)
Active AKTR-HSA-199425 (Reactome)
Active AKTmim-catalysisR-HSA-198347 (Reactome)
Active AKTmim-catalysisR-HSA-198371 (Reactome)
Active AKTmim-catalysisR-HSA-198599 (Reactome)
Active AKTmim-catalysisR-HSA-198609 (Reactome)
Active AKTmim-catalysisR-HSA-198611 (Reactome)
Active AKTmim-catalysisR-HSA-198613 (Reactome)
Active AKTmim-catalysisR-HSA-198621 (Reactome)
Active AKTmim-catalysisR-HSA-199298 (Reactome)
Active AKTmim-catalysisR-HSA-199299 (Reactome)
Active AKTmim-catalysisR-HSA-199839 (Reactome)
Active AKTmim-catalysisR-HSA-199863 (Reactome)
Active AKTmim-catalysisR-HSA-200143 (Reactome)
BADR-HSA-198347 (Reactome)
CASP9(1-416)R-HSA-198621 (Reactome)
CDKN1A/BR-HSA-198613 (Reactome)
CHUKR-HSA-198611 (Reactome)
CREB1R-HSA-199298 (Reactome)
FOXO1,FOXO3,FOXO4R-HSA-199299 (Reactome)
GSK3R-HSA-198371 (Reactome)
H2OR-HSA-199425 (Reactome)
H2OR-HSA-199456 (Reactome)
H2OR-HSA-6811504 (Reactome)
IER3ArrowR-HSA-6811454 (Reactome)
IER3R-HSA-6811472 (Reactome)
MDM2R-HSA-198599 (Reactome)
NR4A1R-HSA-199863 (Reactome)
PDPK1:PIP2ArrowR-HSA-2219524 (Reactome)
PDPK1:PIP2ArrowR-HSA-2243942 (Reactome)
PDPK1:PIP2R-HSA-2243937 (Reactome)
PDPK1:PIP3ArrowR-HSA-198270 (Reactome)
PDPK1:PIP3ArrowR-HSA-2316429 (Reactome)
PDPK1:PIP3R-HSA-2317314 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2ArrowR-HSA-2243937 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2R-HSA-2243942 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2mim-catalysisR-HSA-2243942 (Reactome)
PDPK1R-HSA-2219524 (Reactome)
PDPK1R-HSA-2316429 (Reactome)
PHLPP (Mn2+ cofactor)mim-catalysisR-HSA-199425 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2316434 (Reactome)
PI(3,4,5)P3R-HSA-199456 (Reactome)
PI(3,4,5)P3R-HSA-2316429 (Reactome)
PI(3,4,5)P3R-HSA-2317332 (Reactome)
PI(4,5)P2ArrowR-HSA-1675776 (Reactome)
PI(4,5)P2ArrowR-HSA-1676082 (Reactome)
PI(4,5)P2ArrowR-HSA-199456 (Reactome)
PI(4,5)P2R-HSA-2219524 (Reactome)
PI(4,5)P2R-HSA-2219536 (Reactome)
PI(4,5)P2R-HSA-2316434 (Reactome)
PI3K mutants,Activator:PI3KR-HSA-2400009 (Reactome)
PI3K Inhibitors:PI3KArrowR-HSA-2400009 (Reactome)
PI3K inhibitorsR-HSA-2400009 (Reactome)
PI4PR-HSA-1676082 (Reactome)
PI5PArrowR-HSA-8857925 (Reactome)
PI5PR-HSA-1675776 (Reactome)
PI5PTBarR-HSA-6811504 (Reactome)
PIP4K2 dimersmim-catalysisR-HSA-1675776 (Reactome)
PIP5K1A-Cmim-catalysisR-HSA-1676082 (Reactome)
PP2A-A:PP2A-CArrowR-HSA-6811454 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersArrowR-HSA-6811472 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersR-HSA-6811454 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersmim-catalysisR-HSA-6811454 (Reactome)
PP2A-B56-beta,gammaR-HSA-6811472 (Reactome)
PP2A-B56-beta,gammamim-catalysisR-HSA-6811504 (Reactome)
PP2AR-HSA-8857925 (Reactome)
PTEN GeneR-HSA-5632939 (Reactome)
PTEN GeneR-HSA-5632993 (Reactome)
PTEN mRNA:miR-26A RISCArrowR-HSA-2318752 (Reactome)
PTEN mRNA:miR-26A RISCTBarR-HSA-2321904 (Reactome)
PTEN mRNAArrowR-HSA-5632993 (Reactome)
PTEN mRNAR-HSA-2318752 (Reactome)
PTEN mRNAR-HSA-2321904 (Reactome)
PTEN:Mg2+ArrowR-HSA-2321904 (Reactome)
PTEN:Mg2+mim-catalysisR-HSA-199456 (Reactome)
PiArrowR-HSA-199425 (Reactome)
PiArrowR-HSA-199456 (Reactome)
PiArrowR-HSA-6811504 (Reactome)
R-HSA-1675776 (Reactome) At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A), beta (PIP4K2B) and gamma (PIP4K2C) homodimers and heterodimers (Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015) phosphorylate phosphatidylinositol 5-phosphate (PI5P) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).

The following lists the above proteins with their corresponding literature references: PIP4K2A (Rameh et al. 1997, Clarke et al. 2008, Clarke and Irvine 2013), PIP4K2B (Rameh et al. 1997, Clarke and Irvine 2013) and PIP4K2C (Clarke and Irvine 2013, Clarke et al. 2015).
R-HSA-1676082 (Reactome) At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).

The following lists the above proteins with their corresponding literature references: PIP5K1A (Halstead et al. 2006, Zhang et al. 1997), PIP5K1B (Zhang et al. 1997), and PIP5K1C (Di Paolo et al. 2002).

This reaction is of particular interest because its regulation by small GTPases of the RHO and ARF families, not yet annotated here, ties the process of phosphatidylinositol phosphate biosynthesis to regulation of the actin cytoskeleton and vesicular trafficking, and hence to diverse aspects of cell motility and signalling (Oude Weernink et al. 2004, 2007).
R-HSA-198270 (Reactome) Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-198298 (Reactome) AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A (Borgatti et al. 2003).
R-HSA-198347 (Reactome) Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
R-HSA-198371 (Reactome) GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1.
R-HSA-198599 (Reactome) AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Mayo and Donner 2001, Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of the E3 ubiquitin-protein ligase MDM2 promotes nuclear localization and interferes with the interaction between MDM2 and p14-ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001, Mayo and Donner 2001).
R-HSA-198609 (Reactome) AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a protein complex with TSC1 and this complex acts as a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.
The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
R-HSA-198611 (Reactome) AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival.
R-HSA-198613 (Reactome) Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
R-HSA-198621 (Reactome) AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it.
R-HSA-198640 (Reactome) Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.
Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-199298 (Reactome) AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival.
R-HSA-199299 (Reactome) Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1.
R-HSA-199425 (Reactome) The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT.
R-HSA-199443 (Reactome) The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
R-HSA-199456 (Reactome) The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Maehema et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase. The role of other phosphoinositide phosphatases (INPP5D, INPPL1, INPP5K, PTPRQ, INPP4B) in the negative regulation of PI3K/AKT signaling will be described in future editions of Reactome.
R-HSA-199839 (Reactome) Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT.
R-HSA-199863 (Reactome) AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362).
R-HSA-200143 (Reactome) PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004).
R-HSA-2219524 (Reactome) PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999).
R-HSA-2219536 (Reactome) Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008).
R-HSA-2243937 (Reactome) A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473.
R-HSA-2243938 (Reactome) PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008).
R-HSA-2243942 (Reactome) PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999).
R-HSA-2316429 (Reactome) PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
R-HSA-2316434 (Reactome) A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.

In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
R-HSA-2317314 (Reactome) Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005)
R-HSA-2317332 (Reactome) PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied.
R-HSA-2318752 (Reactome) MIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009).

The MIR26A2 locus is frequently amplified in glioma tumors that retain one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to down-regulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and negatively correlates with the loss of heterozygosity at the PTEN locus in a mouse PTEN +/- glioma model, based on monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
R-HSA-2321904 (Reactome) PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing PTEN protein expression from the remaining allele (Huse et al. 2009).
R-HSA-2400009 (Reactome) A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009.
R-HSA-2400010 (Reactome) AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009.
R-HSA-5632939 (Reactome) PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) binds to the p53-binding site at the PTEN promoter level (Stambolic et al. 2001).
R-HSA-5632993 (Reactome) PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) stimulates PTEN transcription (Stambolic et al. 2000, Singh et al. 2002). PTEN, acting as a negative regulator of PI3K/AKT signaling, affects cell survival, cell cycling, proliferation and migration. PTEN regulates TP53 stability by inhibiting AKT-mediated activation of TP53 ubiquitin ligase MDM2, and thus enhances TP53 transcriptional activity and its own transcriptional activation by TP53. Beside their cross-regulation, PTEN and TP53 can interact and cooperate to regulate survival or apoptotic phenomena (Stambolic et al. 2000, Singh et al. 2002, Nakanishi et al. 2014).
R-HSA-6811454 (Reactome) Activated MAPK1 (ERK2) or MAPK3 (ERK1), recruited to the PP2A complex through IER3 (IEX-1), phosphorylate the regulatory subunit PPP2R5B (B56-beta) or PPP2R5C (B56-gamma) of the PP2A complex on serine residue S368 or S337, respectively. ERK-mediated phosphorylation of the PP2A regulatory subunits causes dissociation of the PP2A complex and prevents PP2A-mediated dephosphorylation of AKT1 (Letourneux et al. 2006, Rocher et al. 2007).
R-HSA-6811472 (Reactome) IER3 (IEX-1) recruits both an activated MAPK (MAPK1 (ERK2) or MAPK3 (ERK1)) and the protein phosphatase 2A (PP2A) complex containing regulatory subunits B56-beta (PPP2R5B) or B56-gamma (PPP2R5C), through an interaction with the B56 subunit, forming a tripartite complex (Letourneux et al. 2006, Rocher et al. 2007).
R-HSA-6811504 (Reactome) The protein phosphatase 2A (PP2A) complex containing a regulatory subunit B56 beta (PPP2R5B) or B56 gamma (PPP2R5C) dephosphorylates activated AKT1 on threonine residue T308 and serine residue S473, thus halting PI3K/AKT signaling (Rocher et al. 2007). Phosphatidylinositol-5-phosphate (PI5P) negatively regulates PP2A-mediated dephosphorylation of AKT1 by promoting, through an unknown mechanism, an inhibitory phosphorylation on tyrosine residue Y307 (Chen et al. 1992) of the catalytic subunit of PP2A (Ramel et al. 2009).
R-HSA-8857925 (Reactome) SRC family tyrosine kinases, such as SRC and LCK, as well as receptor tyrosine kinases, such as EGFR and insulin receptor, can phosphorylate the catalytic subunit of serine/threonine protein phosphatase PP2A at tyrosine residue Y307. Phosphorylation at Y307 inhibits the catalytic activity of PP2A. Phosphatidylinositol-5-phosphate (PI5P) positively regulates phosphorylation of the catalytic subunit of PP2A at Y307.
RPS6KB2R-HSA-199839 (Reactome)
THEM4/TRIB3R-HSA-199443 (Reactome)
TORC2 complexmim-catalysisR-HSA-198640 (Reactome)
TORC2 complexmim-catalysisR-HSA-2243938 (Reactome)
TP53 Tetramer:PTEN GeneArrowR-HSA-5632939 (Reactome)
TP53 Tetramer:PTEN GeneArrowR-HSA-5632993 (Reactome)
TP53 TetramerR-HSA-5632939 (Reactome)
TSC2R-HSA-198609 (Reactome)
miR-26A RISCR-HSA-2318752 (Reactome)
p-FOXO1,p-FOXO3,p-FOXO4ArrowR-HSA-199299 (Reactome)
p-S-AKT:PDPK1:PIP3ArrowR-HSA-2317314 (Reactome)
p-S-AKT:PDPK1:PIP3R-HSA-198270 (Reactome)
p-S-AKT:PDPK1:PIP3mim-catalysisR-HSA-198270 (Reactome)
p-S-AKT:PIP3ArrowR-HSA-198640 (Reactome)
p-S-AKT:PIP3R-HSA-2317314 (Reactome)
p-S133-CREB1ArrowR-HSA-199298 (Reactome)
p-S15,S356-RPS6KB2ArrowR-HSA-199839 (Reactome)
p-S166,S188-MDM2ArrowR-HSA-198599 (Reactome)
p-S183,T246-AKT1S1ArrowR-HSA-200143 (Reactome)
p-S196-CASP9(1-416)ArrowR-HSA-198621 (Reactome)
p-S351-NR4A1ArrowR-HSA-199863 (Reactome)
p-S368-PPP2R5B,p-S337-PPP2R5CArrowR-HSA-6811454 (Reactome)
p-S473-AKT1 E17K mutant:PIP2ArrowR-HSA-2243938 (Reactome)
p-S473-AKT1 E17K mutant:PIP2R-HSA-2243937 (Reactome)
p-S9/21-GSK3ArrowR-HSA-198371 (Reactome)
p-S939,T1462-TSC2ArrowR-HSA-198609 (Reactome)
p-S99-BADArrowR-HSA-198347 (Reactome)
p-T,Y MAPK dimersArrowR-HSA-6811454 (Reactome)
p-T,Y MAPK dimersR-HSA-6811472 (Reactome)
p-T-AKTArrowR-HSA-199425 (Reactome)
p-T-CDKN1A/BArrowR-HSA-198613 (Reactome)
p-T23-CHUKArrowR-HSA-198611 (Reactome)
p-T308,S473-AKT1 E17KArrowR-HSA-2243942 (Reactome)
p-T308,S473-AKT1R-HSA-6811504 (Reactome)
p-Y307-PP2AArrowR-HSA-8857925 (Reactome)
Personal tools