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.
Marino M, Ascenzi P.; ''Steroid hormone rapid signaling: the pivotal role of S-palmitoylation.''; PubMedEurope PMCScholia
Heldin CH, Ostman A, Rönnstrand L.; ''Signal transduction via platelet-derived growth factor receptors.''; PubMedEurope PMCScholia
Chen J, Martin BL, Brautigan DL.; ''Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, Vande Woude GF.; ''Mechanism of met oncogene activation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Shen Y, Naujokas M, Park M, Ireton K.; ''InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase.''; PubMedEurope PMCScholia
Beenken A, Mohammadi M.; ''The FGF family: biology, pathophysiology and therapy.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Fu SM, Winchester RJ, Kunkel HG.; ''Similar idiotypic specificity for the membrane IgD and IgM of human B lymphocytes.''; PubMedEurope PMCScholia
Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMedEurope PMCScholia
Beviglia L, Kramer RH.; ''HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells.''; PubMedEurope PMCScholia
Wang D, Li Z, Messing EM, Wu G.; ''Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Lin CH, Liu SY, Lee EH.; ''SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1.''; PubMedEurope PMCScholia
Handa RJ, Ogawa S, Wang JM, Herbison AE.; ''Roles for oestrogen receptor β in adult brain function.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Masson K, Rönnstrand L.; ''Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3.''; PubMedEurope PMCScholia
Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L.; ''Cracking the estrogen receptor's posttranslational code in breast tumors.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Toledo F, Wahl GM.; ''MDM2 and MDM4: p53 regulators as targets in anticancer therapy.''; PubMedEurope PMCScholia
Rena G, Guo S, Cichy SC, Unterman TG, Cohen P.; ''Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kabuyama Y, Nakatsu N, Homma Y, Fukui Y.; ''Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Liu P, Cheng H, Roberts TM, Zhao JJ.; ''Targeting the phosphoinositide 3-kinase pathway in cancer.''; PubMedEurope PMCScholia
Reber L, Da Silva CA, Frossard N.; ''Stem cell factor and its receptor c-Kit as targets for inflammatory diseases.''; PubMedEurope PMCScholia
del Peso L, González-García M, Page C, Herrera R, Nuñez G.; ''Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.''; PubMedEurope PMCScholia
Hays JL, Watowich SJ.; ''Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Burgering BM, Coffer PJ.; ''Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction.''; PubMedEurope PMCScholia
Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Bradshaw JM.; ''The Src, Syk, and Tec family kinases: distinct types of molecular switches.''; PubMedEurope PMCScholia
Vasudevan KM, Burikhanov R, Goswami A, Rangnekar VM.; ''Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM.; ''Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL.; ''Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rodrigues GA, Park M.; ''Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Gilmore-Hebert M, Ramabhadran R, Stern DF.; ''Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways.''; PubMedEurope PMCScholia
Park H, Poo MM.; ''Neurotrophin regulation of neural circuit development and function.''; PubMedEurope PMCScholia
Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G.; ''Targeting MET in cancer: rationale and progress.''; PubMedEurope PMCScholia
Scheid MP, Marignani PA, Woodgett JR.; ''Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Dailey L, Ambrosetti D, Mansukhani A, Basilico C.; ''Mechanisms underlying differential responses to FGF signaling.''; PubMedEurope PMCScholia
Veiga E, Cossart P.; ''Listeria hijacks the clathrin-dependent endocytic machinery to invade mammalian cells.''; PubMedEurope PMCScholia
Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Liu Y.; ''Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER.; ''A conserved mechanism for steroid receptor translocation to the plasma membrane.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Cheng QC, Tikhomirov O, Zhou W, Carpenter G.; ''Ectodomain cleavage of ErbB-4: characterization of the cleavage site and m80 fragment.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Inoki K, Li Y, Zhu T, Wu J, Guan KL.; ''TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Oude Weernink PA, López de Jesús M, Schmidt M.; ''Phospholipase D signaling: orchestration by PIP2 and small GTPases.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Penington DJ, Bryant I, Riese DJ.; ''Constitutively active ErbB4 and ErbB2 mutants exhibit distinct biological activities.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ni CY, Murphy MP, Golde TE, Carpenter G.; ''gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.''; PubMedEurope PMCScholia
Jeffrey PD, Gorina S, Pavletich NP.; ''Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Meng Z, Jia LF, Gan YH.; ''PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM.; ''Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG.; ''Direct identification of PTEN phosphorylation sites.''; PubMedEurope PMCScholia
Schlessinger J.; ''Common and distinct elements in cellular signaling via EGF and FGF receptors.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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).''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K.; ''Purification and characterization of human Syk produced using a baculovirus expression system.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS.; ''Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Carter RH, Park DJ, Rhee SG, Fearon DT.; ''Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes.''; PubMedEurope PMCScholia
Du K, Montminy M.; ''CREB is a regulatory target for the protein kinase Akt/PKB.''; PubMedEurope PMCScholia
Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Fredriksson L, Li H, Eriksson U.; ''The PDGF family: four gene products form five dimeric isoforms.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Saldaña-Meyer R, Recillas-Targa F.; ''Transcriptional and epigenetic regulation of the p53 tumor suppressor gene.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Takagi M, Absalon MJ, McLure KG, Kastan MB.; ''Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G.; ''Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Shen SM, Guo M, Xiong Z, Yu Y, Zhao XY, Zhang FF, Chen GQ.; ''AIF inhibits tumor metastasis by protecting PTEN from oxidation.''; PubMedEurope PMCScholia
Lu B, Pang PT, Woo NH.; ''The yin and yang of neurotrophin action.''; PubMedEurope PMCScholia
Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rio C, Buxbaum JD, Peschon JJ, Corfas G.; ''Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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).''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Riese DJ, Komurasaki T, Plowman GD, Stern DF.; ''Activation of ErbB4 by the bifunctional epidermal growth factor family hormone epiregulin is regulated by ErbB2.''; PubMedEurope PMCScholia
Cohen BD, Green JM, Foy L, Fell HP.; ''HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers.''; PubMedEurope PMCScholia
Heldin CH, Westermark B.; ''Mechanism of action and in vivo role of platelet-derived growth factor.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Borowiak M, Garratt AN, Wüstefeld T, Strehle M, Trautwein C, Birchmeier C.; ''Met provides essential signals for liver regeneration.''; PubMedEurope PMCScholia
Bibel M, Barde YA.; ''Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system.''; PubMedEurope PMCScholia
Du K, Herzig S, Kulkarni RN, Montminy M.; ''TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK.; ''Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.''; PubMedEurope PMCScholia
Oess S, Icking A, Fulton D, Govers R, Müller-Esterl W.; ''Subcellular targeting and trafficking of nitric oxide synthases.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Amin DN, Perkins AS, Stern DF.; ''Gene expression profiling of ErbB receptor and ligand-dependent transcription.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Skaper SD.; ''The neurotrophin family of neurotrophic factors: an overview.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP.; ''A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.''; PubMedEurope PMCScholia
Trusolino L, Bertotti A, Comoglio PM.; ''MET signalling: principles and functions in development, organ regeneration and cancer.''; PubMedEurope PMCScholia
Lange CA, Gioeli D, Hammes SR, Marker PC.; ''Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Carpenter G.; ''Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways.''; PubMedEurope PMCScholia
Pedram A, Razandi M, Deschenes RJ, Levin ER.; ''DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors.''; PubMedEurope PMCScholia
Petrini I.; ''Biology of MET: a double life between normal tissue repair and tumor progression.''; PubMedEurope PMCScholia
Leslie NR, Kriplani N, Hermida MA, Alvarez-Garcia V, Wise HM.; ''The PTEN protein: cellular localization and post-translational regulation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Gauld SB, Cambier JC.; ''Src-family kinases in B-cell development and signaling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Irish JM, Czerwinski DK, Nolan GP, Levy R.; ''Kinetics of B cell receptor signaling in human B cell subsets mapped by phosphospecific flow cytometry.''; PubMedEurope PMCScholia
Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M.; ''S-palmitoylation modulates human estrogen receptor-alpha functions.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rudd CE.; ''Adaptors and molecular scaffolds in immune cell signaling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
van Leeuwen JE, Samelson LE.; ''T cell antigen-receptor signal transduction.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Nel AE, Landreth GE, Goldschmidt-Clermont PJ, Tung HE, Galbraith RM.; ''Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Pacher P, Beckman JS, Liaudet L.; ''Nitric oxide and peroxynitrite in health and disease.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Van Themsche C, Leblanc V, Parent S, Asselin E.; ''X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization.''; PubMedEurope PMCScholia
Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMedEurope PMCScholia
Farach-Carson MC, Davis PJ.; ''Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Fu SM, Winchester RJ, Kunkel HG.; ''Occurrence of surface IgM, IgD, and free light chains of human lymphocytes.''; PubMedEurope PMCScholia
Schulze WX, Deng L, Mann M.; ''Phosphotyrosine interactome of the ErbB-receptor kinase family.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMedEurope PMCScholia
Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW.; ''Regulation of PTEN transcription by p53.''; PubMedEurope PMCScholia
Maddika S, Kavela S, Rani N, Palicharla VR, Pokorny JL, Sarkaria JN, Chen J.; ''WWP2 is an E3 ubiquitin ligase for PTEN.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Jones FE, Welte T, Fu XY, Stern DF.; ''ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC.; ''HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Schwartz N, Verma A, Bivens CB, Schwartz Z, Boyan BD.; ''Rapid steroid hormone actions via membrane receptors.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Saouaf SJ, Kut SA, Fargnoli J, Rowley RB, Bolen JB, Mahajan S.; ''Reconstitution of the B cell antigen receptor signaling components in COS cells.''; PubMedEurope PMCScholia
Bokoch GM, Vlahos CJ, Wang Y, Knaus UG, Traynor-Kaplan AE.; ''Rac GTPase interacts specifically with phosphatidylinositol 3-kinase.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Oude Weernink PA, Schmidt M, Jakobs KH.; ''Regulation and cellular roles of phosphoinositide 5-kinases.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Chao MV.; ''Neurotrophins and their receptors: a convergence point for many signalling pathways.''; PubMedEurope PMCScholia
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF.; ''Met, metastasis, motility and more.''; PubMedEurope PMCScholia
Wade M, Li YC, Wahl GM.; ''MDM2, MDMX and p53 in oncogenesis and cancer therapy.''; PubMedEurope PMCScholia
Coggeshall KM, McHugh JC, Altman A.; ''Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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 .''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rameh LE, Tolias KF, Duckworth BC, Cantley LC.; ''A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Shinohara H, Kurosaki T.; ''Comprehending the complex connection between PKCbeta, TAK1, and IKK in BCR signaling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ikenoue T, Inoki K, Zhao B, Guan KL.; ''PTEN acetylation modulates its interaction with PDZ domain.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Marlin MC, Li G.; ''Biogenesis and function of the NGF/TrkA signaling endosome.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Biswas DK, Singh S, Shi Q, Pardee AB, Iglehart JD.; ''Crossroads of estrogen receptor and NF-kappaB signaling.''; PubMedEurope PMCScholia
Arasada RR, Carpenter G.; ''Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment.''; PubMedEurope PMCScholia
Lennartsson J, Rönnstrand L.; ''The stem cell factor receptor/c-Kit as a drug target in cancer.''; PubMedEurope PMCScholia
Marino M, Ascenzi P, Acconcia F.; ''S-palmitoylation modulates estrogen receptor alpha localization and functions.''; PubMedEurope PMCScholia
La Rosa P, Pesiri V, Leclercq G, Marino M, Acconcia F.; ''Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity.''; PubMedEurope PMCScholia
Gao T, Furnari F, Newton AC.; ''PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Zeng F, Xu J, Harris RC.; ''Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Schaeper U, Gehring NH, Fuchs KP, Sachs M, Kempkes B, Birchmeier W.; ''Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Slavik JM, Hutchcroft JE, Bierer BE.; ''CD28/CTLA-4 and CD80/CD86 families: signaling and function.''; PubMedEurope PMCScholia
Das S, Dixon JE, Cho W.; ''Membrane-binding and activation mechanism of PTEN.''; PubMedEurope PMCScholia
Uygur B, Abramo K, Leikina E, Vary C, Liaw L, Wu WS.; ''SLUG is a direct transcriptional repressor of PTEN tumor suppressor.''; PubMedEurope PMCScholia
Sweeney C, Lai C, Riese DJ, Diamonti AJ, Cantley LC, Carraway KL.; ''Ligand discrimination in signaling through an ErbB4 receptor homodimer.''; PubMedEurope PMCScholia
Letourneux C, Rocher G, Porteu F.; ''B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rudd CE, Schneider H.; ''Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kim H, Huang W, Jiang X, Pennicooke B, Park PJ, Johnson MD.; ''Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Rönnstrand L.; ''Signal transduction via the stem cell factor receptor/c-Kit.''; PubMedEurope PMCScholia
Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMedEurope PMCScholia
Eswarakumar VP, Lax I, Schlessinger J.; ''Cellular signaling by fibroblast growth factor receptors.''; PubMedEurope PMCScholia
Maehama T, Dixon JE.; ''The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMedEurope PMCScholia
Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K.; ''Association of B cell antigen receptor with protein tyrosine kinase Lyn.''; PubMedEurope PMCScholia
Acuto O, Michel F.; ''CD28-mediated co-stimulation: a quantitative support for TCR signalling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Hou XJ, Ni KM, Yang JM, Li XM.; ''Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses.''; PubMedEurope PMCScholia
Ornitz DM, Marie PJ.; ''FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Lessmann V, Gottmann K, Malcangio M.; ''Neurotrophin secretion: current facts and future prospects.''; PubMedEurope PMCScholia
Alegre ML, Frauwirth KA, Thompson CB.; ''T-cell regulation by CD28 and CTLA-4.''; PubMedEurope PMCScholia
Hazan R, Margolis B, Dombalagian M, Ullrich A, Zilberstein A, Schlessinger J.; ''Identification of autophosphorylation sites of HER2/neu.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Williams EJ, Furness J, Walsh FS, Doherty P.; ''Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.''; PubMedEurope PMCScholia
Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Zhang CL, Zou Y, Yu RT, Gage FH, Evans RM.; ''Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.''; PubMedEurope PMCScholia
Tay Y, Rinn J, Pandolfi PP.; ''The multilayered complexity of ceRNA crosstalk and competition.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMedEurope PMCScholia
Li Z, Mei Y, Liu X, Zhou M.; ''Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Clarke JH, Wang M, Irvine RF.; ''Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Mayo LD, Donner DB.; ''A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
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.
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).
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).
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.
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.
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.
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.
AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a TSC1-TSC2 protein complex that is 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.
AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of ubiquitin-protein ligase E3 MDM2 promotes nuclear localization and inhibits interaction between MDM2 and p19ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001).
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.
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.
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.
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).
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).
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.
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).
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).
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).
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)
One of the functions of PTEN is to act as a phosphoinositide phosphatase that catalyzes dephosphorylation of PIP3 into PIP2. PTEN thus reduces the amount of available PIP3, counteracting PI3K activity and downregulating AKT signaling. PTEN is frequently targeted by loss of function mutations in cancer and in familial cancer syndromes known as PTHS (PTEN hamartoma tumor syndromes, a collection of diseases including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease). Some PTEN loss-of-function variants are also found in autism spectrum disorder patients. For a recent review of PTEN involvement in cancer, please refer to Hollander et al. 2011.
The majority of missense mutations that impair phosphoinositide phosphatase activity of PTEN cluster in exon 5 of PTEN gene and result in substitution of amino acid residues in the catalytic cleft of the phosphatase domain. Arginine at position 130 is the most frequently substituted PTEN residue in cancer. R130 of human PTEN is the last arginine residue in the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain and is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130 substitution mutants show markedly decreased phosphoinositide phosphatase activity (Han et al. 2000, Koul et al. 2002) and are frequently found in endometrial carcinoma (Kong et al. 1997, Konopka et al. 2007). The cysteine residue at position 124 (C124) of human PTEN, in the conserved H-C-K/R-A-G-K-G-R sequence, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during the dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). Therefore, substitution of this critical C124 abolishes PTEN phosphatase activity (Han et al. 2000, Koul et al. 2002). Substitution of histidine H123 in the conserved H-C-K/R-A-G-K-G-R sequence also impairs PTEN phosphatase activity (Lee et al. 1999).
Missense mutations also target amino acid residues in the N-terminal phosphatase domain that are outside the catalytic cleft. Substitution of histidine at position 93 affects the conserved WPD loop of the phosphatase domain of PTEN, and PTEN H93 mutants show low phosphoinositide phosphatase activity (Lee et al. 1999). Serine residue S170 and histidine residue H173 participate in the formation of hydrogen bonds between the N-terminal phosphatase domain of PTEN and the C-terminal membrane-binding C2 domain (Lee et al. 1999). H173, and to a lesser extent S170, are targeted by missense mutations in cancer, and substitution mutants have impaired phosphoinositide phosphatase activity (Han et al. 2000).
Missense mutations also occur in the C2 domain of PTEN. The C2 domain is implicated in membrane binding and localization of PTEN, but also in PTEN roles unrelated to its phosphoinositide phosphatase function (Raftopoulou et al. 2004). Since the roles of these C2 domain PTEN mutants in cancer have not been clarified, these variants will be annotated when more information becomes available.
Besides missense mutations, nonsense mutations that result in PTEN protein truncation are also frequently found in cancer samples. The three residues most frequently targeted by nonsense mutations are R130, R233 and R335. While R130* mutation directly affects the phosphatase domain of PTEN, R233* and R335* affect the C2 domain. It is has not yet been elucidated whether R233* and R335* affect PTEN membrane localization or impair PTEN function in some other way.
In cancer, PTEN is also frequently inactivated by genomic deletions and loss of heterozygosity (LOH) affecting chromosome band 10q23 or by epigenetic silencing (reviewed by Hollander et al. 2011).
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 retained one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to downregulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and prevent loss of heterozigosity at the PTEN locus in a mouse PTEN +/- glioma model, based on a monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
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).
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.
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 the remaining PTEN protein expression (Huse et al. 2009).
Constitutively active PI3K complex produces PIP3 in the absence of growth stimuli, resulting in aberrant activation of downstream AKT signaling that positively regulates cell growth and survival. The PIK3CA gene, encoding the catalytic subunit of PI3K (p110alpha), is one of the most frequently mutated oncogenes in cancer. Hotspot mutations are found in the helical domain and kinase domain of PIK3CA, with the most frequent mutations being E545K substitution in the helical domain and H1047R substitution in the kinase domain. The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants. In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly. The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly. Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated. Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants. Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011). Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011). For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009.
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.
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).
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).
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).
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.
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.
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).
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1257604
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
PIP3
THEM4/TRIB31. "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.
p-S473-AKT1 E17K mutant
PIP2PDPK1
PIP3Annotated Interactions
PIP3
THEM4/TRIB3p-S473-AKT1 E17K mutant
PIP2p-S473-AKT1 E17K mutant
PIP2Phosphorylation 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).
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.
The majority of missense mutations that impair phosphoinositide phosphatase activity of PTEN cluster in exon 5 of PTEN gene and result in substitution of amino acid residues in the catalytic cleft of the phosphatase domain. Arginine at position 130 is the most frequently substituted PTEN residue in cancer. R130 of human PTEN is the last arginine residue in the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain and is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130 substitution mutants show markedly decreased phosphoinositide phosphatase activity (Han et al. 2000, Koul et al. 2002) and are frequently found in endometrial carcinoma (Kong et al. 1997, Konopka et al. 2007). The cysteine residue at position 124 (C124) of human PTEN, in the conserved H-C-K/R-A-G-K-G-R sequence, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during the dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). Therefore, substitution of this critical C124 abolishes PTEN phosphatase activity (Han et al. 2000, Koul et al. 2002). Substitution of histidine H123 in the conserved H-C-K/R-A-G-K-G-R sequence also impairs PTEN phosphatase activity (Lee et al. 1999).
Missense mutations also target amino acid residues in the N-terminal phosphatase domain that are outside the catalytic cleft. Substitution of histidine at position 93 affects the conserved WPD loop of the phosphatase domain of PTEN, and PTEN H93 mutants show low phosphoinositide phosphatase activity (Lee et al. 1999). Serine residue S170 and histidine residue H173 participate in the formation of hydrogen bonds between the N-terminal phosphatase domain of PTEN and the C-terminal membrane-binding C2 domain (Lee et al. 1999). H173, and to a lesser extent S170, are targeted by missense mutations in cancer, and substitution mutants have impaired phosphoinositide phosphatase activity (Han et al. 2000).
Missense mutations also occur in the C2 domain of PTEN. The C2 domain is implicated in membrane binding and localization of PTEN, but also in PTEN roles unrelated to its phosphoinositide phosphatase function (Raftopoulou et al. 2004). Since the roles of these C2 domain PTEN mutants in cancer have not been clarified, these variants will be annotated when more information becomes available.
Besides missense mutations, nonsense mutations that result in PTEN protein truncation are also frequently found in cancer samples. The three residues most frequently targeted by nonsense mutations are R130, R233 and R335. While R130* mutation directly affects the phosphatase domain of PTEN, R233* and R335* affect the C2 domain. It is has not yet been elucidated whether R233* and R335* affect PTEN membrane localization or impair PTEN function in some other way.
In cancer, PTEN is also frequently inactivated by genomic deletions and loss of heterozygosity (LOH) affecting chromosome band 10q23 or by epigenetic silencing (reviewed by Hollander et al. 2011).
The MIR26A2 locus is frequently amplified in glioma tumors that retained one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to downregulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and prevent loss of heterozigosity at the PTEN locus in a mouse PTEN +/- glioma model, based on a monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
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).
The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants.
In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly.
The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly.
Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated.
Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants.
Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011).
Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011).
For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009.
PDPK1
PIP3PDPK1
PIP3