PIP3 activates AKT signaling (Homo sapiens)

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20157, 241114, 294, 30673, 275172, 28855, 85, 89, 90, 93...8181, 20642, 27322, 102, 165, 223, 22586, 93, 106, 263201243, 5170, 175, 2965109121, 156, 236, 278, 284264, 267172, 201, 28873, 2751151881, 206162, 253, 260172, 201, 288172, 288265, 31157, 241, 27543, 67, 70, 127, 30147, 129, 166, 24812236, 2261621582352, 1079972nucleoplasmcytosolPDPK1 p-T-CDKN1A/BKL-2 p-T202,Y204-MAPK3 p-Y307-PPP2CB FOXO1,FOXO3,FOXO4p-S9-GSK3B FGF22 PPP2R5C IER3 p-T305,S472-AKT3 RAF/MAP kinasecascadep-S21-GSK3A p-7Y-KIT ATPPiPPP2R1A TORC2 complexp-T309,S474-AKT2 p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform Signaling by FGFRBKM120 p-T305-AKT3 PPP2R5E PPP2R5D p-T185,Y187-MAPK1 THEM4 GalNAc-T178-FGF23(25-251) Regulation of TP53Expression andDegradationLCK p-S196-CASP9(1-416)p-T157-CDKN1B PTEN mRNAp-T-AKTp-10Y-ERBB3-1 p-5Y-GAB1 EIF2C3 PIK3CA LY294002 EGF-like ligands XL147 p-FOXO1,p-FOXO3,p-FOXO4p-Y191-CD28 PPP2CA Signaling by METCDKN1A PI(3,4,5)P3Mn2+ TP53 p-T23-CHUKp-T308,S473-AKT1 TNRC6A PI3K inhibitorsFGF16 GSK1059615 PPP2R1A GRB2-1 ADPFGF20 XL765 PTEN mRNA:miR-26ARISCPI4PTP53 Tetramer:PTENGeneGDC0941 PX-866 p-S166,S188-MDM2PPP2R1A Activator:PI3K PPP2R1A Activator:PI3KRPS6KB2Signaling by ERBB2PPP2CB miR-26A RISCPTEN gene p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform PDGFA-1 PPP2R5C p-T145-CDKN1A Costimulation by theCD28 familyTHEM4 TNRC6C PiGDC0941 PI5Pp-6Y-ERBB2 FGF19 IRAK4 PX-866 AKT2 EIF2C3 p-S473-AKT1 PIK3R2 FGF9 p-T305,S472-AKT3 AKT3 BGT226 Signaling by ERBB4p-T308,S473-AKT1 PiPIP5K1C PDGFA-2 p-S473-AKT1 E17K p-6Y-CD19 Activated FGFR2b homodimer bound to FGF PTENTP53 RegulatesMetabolic GenesAKT1 E17K p-6Y-INSR(763-1382) PP2A-A:PP2A-CPI(3,4,5)P3 p-S474-AKT2 ATPPI3K mutants ATPFOXO1 p-S472-AKT3 p-Y394-LCK p-S474-AKT2 p-Y307-PPP2CA ADPmiR-26A1 IL1RAP-1 p-S473-AKT1 p-S337-PPP2R5C XL765 TRIB3 PPP2R1B ADPp-6Y-FRS2 p-S472-AKT3 AKT1 E17Kp-T32,S142,S207-FOXO4-2 Signaling by SCF-KITp-T308,S473-AKT1PI(3,4,5)P3 KITLG-1(26-190) H2OPIK3R1 BADPIP4K2 dimersATPATPp-S939,T1462-TSC2Signaling by the BCell Receptor (BCR)PDPK1 p-Y,Y877-ERBB2 CDKN1A,CDKN1BPIP5K1A-Cp-S133-CREB1PPP2R1B PPP2R1B miR-26A2 p-S-AKT:PIP3EIF2C4 PDPK1 AKT1 FOXO4-1 CREB1Neuregulins PIP4K2B TNRC6C PI3Kmutants,Activator:PI3KADPADPPI(4,5)P2 p-S351-NR4A1p-6Y-FGFR3c PI(4,5)P2 p-8Y-FGFR1c p-S183,T246-AKT1S1ActivatedSRC,LCK,EGFR,INSRAKT/AKT1 E17K mutantPPP2CB ATPActive AKTH2OPPP2R5A PP2A-B56-beta,gammaPIP4K2C CHUKFGF3 AKT1IER3EGF MK2206 PIK3CB p-S197,S262,T32-FOXO4 ATPp-T24,S256,S319-FOXO1 Active AKTPPP2R5B FGF23(25-251) PP2Ap-Y307-PP2APIP4K2A p-S368-PPP2R5B,p-S337-PPP2R5Cp-S99-BADAKT:PIP3AKT TNRC6B PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersPTEN mRNA MKRN1ATPPPP2R5B THEM4/TRIB3FGF10 EGF ADPp-Y180-ICOS GRB2-1 p-Y-IRS1 Activator:PI3K ADPp-T32,S253,S315-FOXO3 ADPIL33 AKT:PIP3:THEM4/TRIB3H2OActivated FGFR2c homodimer bound to FGF Intrinsic Pathwayfor Apoptosisp-S368-PPP2R5B GAB1 miR-26A2 PI(3,4,5)P3 p-S15,S356-RPS6KB2PI3K Inhibitors:PI3Kp-S473-AKT1 E17Kmutant:PIP2p-7Y,Y1112-ERBB2 PPP2R5B BKM120 FGF18 NRG1 FGF17-1 p-Y-ERBB2 CD86 EIF2C1 Mitotic G1-G1/SphasesKLB p-11Y-PDGFRA EIF2C1 AKT1S1EIF2C2 MDM2PI(4,5)P2 PDPK1Signaling by EGFRMK2206 AKT1 TRIB3 PPP2R1B PI(3,4,5)P3 MYD88 AKT2 p-T185,Y187-MAPK1 PHLPP1 AKT1 E17K GSK1059615 FGF4 MAPKAP1 IL1RL1 4xHC-INS(90-110) PPP2R5C TNRC6A p-T309-AKT2 VAV1 PDPK1:PIP2ATPp-T308,S473-AKT1E17Kp-Y63,Y79,Y110-TRAT1 AKT1 E17K p-S-AKT:PDPK1:PIP3AKT inhibitors:AKTPHLPP2 PIK3R3 XL147 PPP2R5C p-6Y-EGFR BGT226 PI3K mutants IRAK1 PI(3,4,5)P3 miR-26A1 KL-1 p-Y546,Y584-PTPN11 ATPp-Y419-SRC-1 MTOR PHLPP (Mn2+cofactor)PIK3R1 AKT inhibitorsp-6Y-EGFR GSK3A PPP2R1A PDPK1:p-S473-AKT1E17K mutant:PIP2PPP2CA PRR5 MLST8 AKTRICTOR NR4A1wortmannin GSK3B AKT2 Signaling by PDGFFYN p-6Y-FGFR3b ADPFOXO4-2 HGF(32-494) p-T,Y MAPK dimersperifosine AKT EIF2C2 p-4Y-PIK3AP1 FGF2(10-155) PPP2CA FOXO3 PPP2R5D p-8Y-FGFR1b HGF(495-728) TNRC6B FGF8-1 FGF1 PIP5K1A MOV10 TSC2p-7Y-ERBB2 NRG2 perifosine p-S473-AKT1 E17K Signalling by NGFp-Y-IRS2 p-6Y,Y1112-ERBB2 ADPPIP5K1B TCR signalingp-T202,Y204-MAPK3 BEZ235 PDGFB(82-241) HS PI(4,5)P2 FGF5-1 MOV10 EIF2C4 FGF6 p-S9/21-GSK3PPP2CB PPP2R5E p-S109-MKRN1AKT3 INSR(28-758) TP53 AKT1 PPP2R5A p-5Y-FGFR4 Triciribine PTEN geneGSK3IL33:IL1RL1:IL1RAP-1:MYD88:IRAK1,IRAK4,TRAF6PDPK1 PDGFB (82-190) PPP2R1B 2xHC-INS(25-54) PPP2CA PPP2CB TRAF6 CASP9(1-416)TP53 TetramerAKT3 wortmannin PTEN RegulationTriciribine PI(4,5)P2CD80 p-Y1234,Y1235,Y1349,Y1356-MET p-12Y-PDGFRB LY294002 p-T309,S474-AKT2 PIK3CD PDPK1:PIP3mTOR signallingAKT1 E17Kmutant:PIP2CDKN1B p-T308-AKT1 PPP2R5B BEZ235 909366, 271, 317, 31855, 1129, 40, 62, 63, 194...448, 19, 34, 37, 39...89, 31526317410, 13, 14, 20, 21, 38...31, 192, 299302106126, 136, 1409073, 2751723026, 12, 48, 116, 178...108, 179, 200, 249, 256...2271, 4, 7, 11, 25...1722638689, 31527829827910617211517216217416, 27, 33, 41, 58...227186863079355, 112132, 224, 2423, 5, 15, 23, 26...245245298172196, 228, 2688617217, 45, 60, 82, 131...186321, 32655, 89, 90, 93, 112...307172


Description

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

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  350. Williams EJ, Furness J, Walsh FS, Doherty P.; ''Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.''; PubMed Europe PMC Scholia
  351. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMed Europe PMC Scholia
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  353. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  354. Zhang CL, Zou Y, Yu RT, Gage FH, Evans RM.; ''Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.''; PubMed Europe PMC Scholia
  355. Tay Y, Rinn J, Pandolfi PP.; ''The multilayered complexity of ceRNA crosstalk and competition.''; PubMed Europe PMC Scholia
  356. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C.; ''Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation.''; PubMed Europe PMC Scholia
  357. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC Scholia
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  359. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH.; ''Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN.''; PubMed Europe PMC Scholia
  360. Clarke JH, Wang M, Irvine RF.; ''Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases.''; PubMed Europe PMC Scholia
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  370. Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS.; ''Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation.''; PubMed Europe PMC Scholia
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  373. Shen K, Novak RF.; ''DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells.''; PubMed Europe PMC Scholia
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History

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

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT R-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
AKT inhibitors:AKTComplexR-HSA-2400006 (Reactome)
AKT inhibitorsComplexR-ALL-2399923 (Reactome)
AKT/AKT1 E17K mutantComplexR-HSA-2400013 (Reactome)
AKT1 E17K mutant:PIP2ComplexR-HSA-2219527 (Reactome)
AKT1 E17K ProteinP31749 (Uniprot-TrEMBL)
AKT1 E17KProteinP31749 (Uniprot-TrEMBL)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT1ProteinP31749 (Uniprot-TrEMBL)
AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
AKT2 ProteinP31751 (Uniprot-TrEMBL)
AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
AKT:PIP3:THEM4/TRIB3ComplexR-HSA-199453 (Reactome)
AKT:PIP3ComplexR-HSA-2317329 (Reactome)
AKTComplexR-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated SRC,LCK,EGFR,INSRComplexR-HSA-8857936 (Reactome)
Activated FGFR2b homodimer bound to FGF R-HSA-192606 (Reactome)
Activated FGFR2c homodimer bound to FGF R-HSA-192616 (Reactome)
Activator:PI3K R-HSA-2316432 (Reactome)
Activator:PI3KComplexR-HSA-2316432 (Reactome)
Active AKTComplexR-HSA-202072 (Reactome)
Active AKTComplexR-HSA-202074 (Reactome)
BADProteinQ92934 (Uniprot-TrEMBL)
BEZ235 MetaboliteCHEBI:71952 (ChEBI)
BGT226 MetaboliteCHEBI:71953 (ChEBI)
BKM120 MetaboliteCHEBI:71954 (ChEBI)
CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
CD80 ProteinP33681 (Uniprot-TrEMBL)
CD86 ProteinP42081 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A,CDKN1BComplexR-HSA-182504 (Reactome)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CHUKProteinO15111 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Costimulation by the CD28 familyPathwayR-HSA-388841 (Reactome) Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation.
The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity.
The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules.
EGF ProteinP01133 (Uniprot-TrEMBL)
EGF-like ligands R-HSA-1233230 (Reactome)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C2 ProteinQ9UKV8 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
FGF1 ProteinP05230 (Uniprot-TrEMBL)
FGF10 ProteinO15520 (Uniprot-TrEMBL)
FGF16 ProteinO43320 (Uniprot-TrEMBL)
FGF17-1 ProteinO60258-1 (Uniprot-TrEMBL)
FGF18 ProteinO76093 (Uniprot-TrEMBL)
FGF19 ProteinO95750 (Uniprot-TrEMBL)
FGF2(10-155) ProteinP09038 (Uniprot-TrEMBL)
FGF20 ProteinQ9NP95 (Uniprot-TrEMBL)
FGF22 ProteinQ9HCT0 (Uniprot-TrEMBL)
FGF23(25-251) ProteinQ9GZV9 (Uniprot-TrEMBL)
FGF3 ProteinP11487 (Uniprot-TrEMBL)
FGF4 ProteinP08620 (Uniprot-TrEMBL)
FGF5-1 ProteinP12034-1 (Uniprot-TrEMBL)
FGF6 ProteinP10767 (Uniprot-TrEMBL)
FGF8-1 ProteinP55075-1 (Uniprot-TrEMBL)
FGF9 ProteinP31371 (Uniprot-TrEMBL)
FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
FOXO1,FOXO3,FOXO4ComplexR-HSA-199272 (Reactome)
FOXO3 ProteinO43524 (Uniprot-TrEMBL)
FOXO4-1 ProteinP98177-1 (Uniprot-TrEMBL)
FOXO4-2 ProteinP98177-2 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GDC0941 MetaboliteCHEBI:65326 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GSK1059615 MetaboliteCHEBI:71955 (ChEBI)
GSK3A ProteinP49840 (Uniprot-TrEMBL)
GSK3B ProteinP49841 (Uniprot-TrEMBL)
GSK3ComplexR-HSA-198358 (Reactome)
GalNAc-T178-FGF23(25-251) ProteinQ9GZV9 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HGF(32-494) ProteinP14210 (Uniprot-TrEMBL)
HGF(495-728) ProteinP14210 (Uniprot-TrEMBL)
HS MetaboliteCHEBI:28815 (ChEBI)
IER3 ProteinP46695 (Uniprot-TrEMBL)
IER3ProteinP46695 (Uniprot-TrEMBL)
IL1RAP-1 ProteinQ9NPH3-1 (Uniprot-TrEMBL)
IL1RL1 ProteinQ01638 (Uniprot-TrEMBL)
IL33 ProteinO95760 (Uniprot-TrEMBL)
IL33:IL1RL1:IL1RAP-1:MYD88:IRAK1,IRAK4,TRAF6ComplexR-HSA-8981951 (Reactome)
INSR(28-758) ProteinP06213 (Uniprot-TrEMBL)
IRAK1 ProteinP51617 (Uniprot-TrEMBL)
IRAK4 ProteinQ9NWZ3 (Uniprot-TrEMBL)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

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

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

KITLG-1(26-190) ProteinP21583-1 (Uniprot-TrEMBL)
KL-1 ProteinQ9UEF7-1 (Uniprot-TrEMBL)
KL-2 ProteinQ9UEF7-2 (Uniprot-TrEMBL)
KLB ProteinQ86Z14 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LY294002 MetaboliteCHEBI:65329 (ChEBI)
MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MK2206 MetaboliteCHEBI:716367 (ChEBI)
MKRN1ProteinQ9UHC7 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NR4A1ProteinP22736 (Uniprot-TrEMBL)
NRG1 R-HSA-1233225 (Reactome)
NRG2 ProteinO14511 (Uniprot-TrEMBL)
Neuregulins R-HSA-1227957 (Reactome)
PDGFA-1 ProteinP04085-1 (Uniprot-TrEMBL)
PDGFA-2 ProteinP04085-2 (Uniprot-TrEMBL)
PDGFB (82-190) ProteinP01127 (Uniprot-TrEMBL)
PDGFB(82-241) ProteinP01127 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP2ComplexR-HSA-2219520 (Reactome)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2ComplexR-HSA-2243941 (Reactome)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PHLPP (Mn2+ cofactor)ComplexR-HSA-199450 (Reactome)
PHLPP1 ProteinO60346 (Uniprot-TrEMBL)
PHLPP2 ProteinQ6ZVD8 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K mutants,Activator:PI3KComplexR-HSA-2400011 (Reactome)
PI3K Inhibitors:PI3KComplexR-HSA-2400008 (Reactome)
PI3K inhibitorsComplexR-ALL-2399811 (Reactome) PI3K inhibitors bind the catalytic subunit of PIK3CA, blocking its phosphoinositide kinase activity.
PI3K mutants R-HSA-2394006 (Reactome)
PI4PMetaboliteCHEBI:17526 (ChEBI)
PI5PMetaboliteCHEBI:16500 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIP4K2 dimersComplexR-HSA-1806229 (Reactome)
PIP4K2A ProteinP48426 (Uniprot-TrEMBL)
PIP4K2B ProteinP78356 (Uniprot-TrEMBL)
PIP4K2C ProteinQ8TBX8 (Uniprot-TrEMBL)
PIP5K1A ProteinQ99755 (Uniprot-TrEMBL)
PIP5K1A-CComplexR-HSA-1806157 (Reactome)
PIP5K1B ProteinO14986 (Uniprot-TrEMBL)
PIP5K1C ProteinO60331 (Uniprot-TrEMBL)
PP2A-A:PP2A-CComplexR-HSA-6811485 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersComplexR-HSA-6811477 (Reactome)
PP2A-B56-beta,gammaComplexR-HSA-6811526 (Reactome)
PP2AComplexR-HSA-196206 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5A ProteinQ15172 (Uniprot-TrEMBL)
PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP2R5E ProteinQ16537 (Uniprot-TrEMBL)
PRR5 ProteinP85299 (Uniprot-TrEMBL)
PTEN RegulationPathwayR-HSA-6807070 (Reactome) PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.

Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).

MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).

PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).

Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.

In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.

Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).

PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016).

PTEN gene ProteinENSG00000171862 (Ensembl)
PTEN geneGeneProductENSG00000171862 (Ensembl)
PTEN mRNA ProteinENST00000371953 (Ensembl)
PTEN mRNA:miR-26A RISCComplexR-HSA-2318750 (Reactome)
PTEN mRNARnaENST00000371953 (Ensembl)
PTENProteinP60484 (Uniprot-TrEMBL)
PX-866 MetaboliteCHEBI:65345 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
Regulation of TP53

Expression and

Degradation
PathwayR-HSA-6806003 (Reactome) TP53 (p53) tumor suppressor protein is a transcription factor that functions as a homotetramer (Jeffrey et al. 1995). The protein levels of TP53 are low in unstressed cells due to MDM2-mediated ubiquitination that triggers proteasome-mediated degradation of TP53 (Wu et al. 1993). The E3 ubiquitin ligase MDM2 functions as a homodimer/homo-oligomer or a heterodimer/hetero-oligomer with MDM4 (MDMX) (Linares et al. 2003, Toledo and Wahl 2007, Cheng et al. 2011, Wade et al. 2013).

Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).

While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005).

Signaling by EGFRPathwayR-HSA-177929 (Reactome) The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011.
Signaling by ERBB2PathwayR-HSA-1227986 (Reactome) ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).

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

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

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

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

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


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

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

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

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

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

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

This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
Signaling by METPathwayR-HSA-6806834 (Reactome) MET is a receptor tyrosine kinase (RTK) (Cooper et al. 1984, Park et al. 1984) activated by binding to its ligand, Hepatocyte growth factor/Scatter factor (HGF/SF) (Bottaro et al. 1991, Naldini et al. 1991). Similar to other related RTKs, such as EGFR, ligand binding induces MET dimerization and trans-autophosphorylation, resulting in the active MET receptor complex (Ferracini et al. 1991, Longati et al. 1994, Rodrigues and Park 1994, Kirchhofer et al. 2004, Stamos et al. 2004, Hays and Watowich 2004). Phosphorylated tyrosines in the cytoplasmic tail of MET serve as docking sites for binding of adapter proteins, such as GRB2, SHC1 and GAB1, which trigger signal transduction cascades that activate PI3K/AKT, RAS, STAT3, PTK2, RAC1 and RAP1 signaling (Ponzetto et al. 1994, Pelicci et al. 1995, Weidner et al. 1995, Besser et al. 1997, Shen and Novak 1997, Beviglia and Kramer 1999, Rodrigues et al. 2000, Sakkab et al. 2000, Schaeper et al. 2000, Lamorte et al. 2002, Wang et al. 2002, Chen and Chen 2006, Palamidessi et al. 2008, Chen et al. 2011, Murray et al. 2014).
Activation of PLC gamma 1 (PLCG1) signaling by MET remains unclear. It has been reported that PLCG1 can bind to MET directly (Ponzetto et al. 1994) or be recruited by phosphorylated GAB1 (Gual et al. 2000). Tyrosine residue Y307 of GAB1 that serves as docking sites for PLCG1 may be phosphorylated either by activated MET (Watanabe et al. 2006) or SRC (Chan et al. 2010). Another PCLG1 docking site on GAB1, tyrosine residue Y373, was reported as the SRC target, while the kinase for the main PLCG1 docking site, Y407 of GAB1, is not known (Chan et al. 2010).
Signaling by MET promotes cell growth, cell survival and motility, which are essential for embryonic development (Weidner et al. 1993, Schmidt et al. 1995, Uehara et al. 1995, Bladt et al. 1995, Maina et al. 1997, Maina et al. 2001, Helmbacher et al. 2003) and tissue regeneration (Huh et al. 2004, Borowiak et al. 2004, Liu 2004, Chmielowiec et al. 2007). MET signaling is frequently aberrantly activated in cancer, through MET overexpression or activating MET mutations (Schmidt et al. 1997, Pennacchietti et al. 2003, Smolen et al. 2006, Bertotti et al. 2009).
Considerable progress has recently been made in the development of HGF-MET inhibitors in cancer therapy. These include inhibitors of HGF activators, HGF inhibitors and MET antagonists, which are protein therapeutics that act outside the cell. Kinase inhibitors function inside the cell and have constituted the largest effort towards MET-based therapeutics (Gherardi et al. 2012).
Pathogenic bacteria of the species Listeria monocytogenes, exploit MET receptor as an entryway to host cells (Shen et al. 2000, Veiga and Cossart 2005, Neimann et al. 2007).
For review of MET signaling, please refer to Birchmeier et al. 2003, Trusolino et al. 2010, Gherardi et al. 2012, Petrini 2015.
Signaling by PDGFPathwayR-HSA-186797 (Reactome) Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell.
Signaling by SCF-KITPathwayR-HSA-1433557 (Reactome) Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours.
Signaling by the B Cell Receptor (BCR)PathwayR-HSA-983705 (Reactome) Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesel et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010).
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.
Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006).
Signalling by NGFPathwayR-HSA-166520 (Reactome) Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread.


Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling.
TCR signalingPathwayR-HSA-202403 (Reactome) The TCR is a multisubunit complex that consists of clonotypic alpha/beta chains noncovalently associated with the invariant CD3 delta/epsilon/gamma and TCR zeta chains. T cell activation by antigen presenting cells (APCs) results in the activation of protein tyrosine kinases (PTKs) that associate with CD3 and TCR zeta subunits and the co-receptor CD4. Members of the Src kinases (Lck), Syk kinases (ZAP-70), Tec (Itk) and Csk families of nonreceptor PTKs play a crucial role in T cell activation. Activation of PTKs following TCR engagement results in the recruitment and tyrosine phosphorylation of enzymes such as phospholipase C gamma1 and Vav as well as critical adaptor proteins such as LAT, SLP-76 and Gads. These proximal activation leads to reorganization of the cytoskeleton as well as transcription activation of multiple genes leading to T lymphocyte proliferation, differentiation and/or effector function.
THEM4 ProteinQ5T1C6 (Uniprot-TrEMBL)
THEM4/TRIB3ComplexR-HSA-2400007 (Reactome)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TORC2 complexComplexR-HSA-198626 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Regulates Metabolic GenesPathwayR-HSA-5628897 (Reactome) While the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.

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

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

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

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

TP53 Tetramer:PTEN GeneComplexR-HSA-5632941 (Reactome)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
Triciribine MetaboliteCHEBI:65310 (ChEBI)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
XL147 MetaboliteCHEBI:71957 (ChEBI)
XL765 MetaboliteCHEBI:71958 (ChEBI)
mTOR signallingPathwayR-HSA-165159 (Reactome) Target of rapamycin (mTOR) is a highly-conserved serine/threonine kinase that regulates cell growth and division in response to energy levels, growth signals, and nutrients (Zoncu et al. 2011). Control of mTOR activity is critical for the cell since its dysregulation leads to cancer, metabolic disease, and diabetes (Laplante & Sabatini 2012). In cells, mTOR exists as two structurally distinct complexes termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), each one with specificity for different sets of effectors. mTORC1 couples energy and nutrient abundance to cell growth and proliferation by balancing anabolic (protein synthesis and nutrient storage) and catabolic (autophagy and utilization of energy stores) processes.
miR-26A RISCComplexR-HSA-2318737 (Reactome)
miR-26A1 ProteinMI0000083 (miRBase mature sequence)
miR-26A2 ProteinMI0000750 (miRBase mature sequence)
p-10Y-ERBB3-1 ProteinP21860-1 (Uniprot-TrEMBL)
p-11Y-PDGFRA ProteinP16234 (Uniprot-TrEMBL)
p-12Y-PDGFRB ProteinP09619 (Uniprot-TrEMBL)
p-4Y-PIK3AP1 ProteinQ6ZUJ8 (Uniprot-TrEMBL)
p-5Y-FGFR4 ProteinP22455 (Uniprot-TrEMBL)
p-5Y-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p-6Y,Y1112-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-6Y-CD19 ProteinP15391 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-6Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-6Y-FGFR3b ProteinP22607-2 (Uniprot-TrEMBL)
p-6Y-FGFR3c ProteinP22607-1 (Uniprot-TrEMBL)
p-6Y-FRS2 ProteinQ8WU20 (Uniprot-TrEMBL)
p-6Y-INSR(763-1382) ProteinP06213 (Uniprot-TrEMBL)
p-7Y,Y1112-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-7Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-7Y-KIT ProteinP10721 (Uniprot-TrEMBL)
p-8Y-FGFR1b ProteinP11362-19 (Uniprot-TrEMBL) While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
p-8Y-FGFR1c ProteinP11362-1 (Uniprot-TrEMBL)
p-FOXO1,p-FOXO3,p-FOXO4ComplexR-HSA-199269 (Reactome)
p-S-AKT:PDPK1:PIP3ComplexR-HSA-2317313 (Reactome)
p-S-AKT:PIP3ComplexR-HSA-2317310 (Reactome)
p-S109-MKRN1ProteinQ9UHC7 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S15,S356-RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
p-S166,S188-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S183,T246-AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
p-S196-CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
p-S197,S262,T32-FOXO4 ProteinP98177-1 (Uniprot-TrEMBL)
p-S21-GSK3A ProteinP49840 (Uniprot-TrEMBL)
p-S337-PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
p-S351-NR4A1ProteinP22736 (Uniprot-TrEMBL)
p-S368-PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
p-S368-PPP2R5B,p-S337-PPP2R5CComplexR-HSA-6811475 (Reactome)
p-S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-S473-AKT1 E17K mutant:PIP2ComplexR-HSA-2243943 (Reactome)
p-S473-AKT1 E17K ProteinP31749 (Uniprot-TrEMBL)
p-S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-S9-GSK3B ProteinP49841 (Uniprot-TrEMBL)
p-S9/21-GSK3ComplexR-HSA-198373 (Reactome)
p-S939,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-S99-BADProteinQ92934 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-1268261 (Reactome)
p-T-AKTComplexR-HSA-202084 (Reactome)
p-T-CDKN1A/BComplexR-HSA-198605 (Reactome)
p-T145-CDKN1A ProteinP38936 (Uniprot-TrEMBL)
p-T157-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T23-CHUKProteinO15111 (Uniprot-TrEMBL)
p-T24,S256,S319-FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T305-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 E17KProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)
p-T308-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T309-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T32,S142,S207-FOXO4-2 ProteinP98177-2 (Uniprot-TrEMBL)
p-T32,S253,S315-FOXO3 ProteinO43524 (Uniprot-TrEMBL)
p-Y,Y877-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform ProteinQ15303-2 (Uniprot-TrEMBL)
p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform ProteinQ15303-1 (Uniprot-TrEMBL)
p-Y1234,Y1235,Y1349,Y1356-MET ProteinP08581 (Uniprot-TrEMBL)
p-Y180-ICOS ProteinQ9Y6W8-1 (Uniprot-TrEMBL)
p-Y191-CD28 ProteinP10747 (Uniprot-TrEMBL)
p-Y307-PP2AComplexR-HSA-8857938 (Reactome)
p-Y307-PPP2CA ProteinP67775 (Uniprot-TrEMBL)
p-Y307-PPP2CB ProteinP62714 (Uniprot-TrEMBL)
p-Y394-LCK ProteinP06239 (Uniprot-TrEMBL)
p-Y419-SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
p-Y63,Y79,Y110-TRAT1 ProteinQ6PIZ9 (Uniprot-TrEMBL)
perifosine MetaboliteCHEBI:428891 (ChEBI)
wortmannin MetaboliteCHEBI:52289 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-1675776 (Reactome)
ADPArrowR-HSA-1676082 (Reactome)
ADPArrowR-HSA-198270 (Reactome)
ADPArrowR-HSA-198347 (Reactome)
ADPArrowR-HSA-198371 (Reactome)
ADPArrowR-HSA-198599 (Reactome)
ADPArrowR-HSA-198609 (Reactome)
ADPArrowR-HSA-198611 (Reactome)
ADPArrowR-HSA-198613 (Reactome)
ADPArrowR-HSA-198621 (Reactome)
ADPArrowR-HSA-198640 (Reactome)
ADPArrowR-HSA-199298 (Reactome)
ADPArrowR-HSA-199299 (Reactome)
ADPArrowR-HSA-199839 (Reactome)
ADPArrowR-HSA-199863 (Reactome)
ADPArrowR-HSA-200143 (Reactome)
ADPArrowR-HSA-2243938 (Reactome)
ADPArrowR-HSA-2243942 (Reactome)
ADPArrowR-HSA-2316434 (Reactome)
ADPArrowR-HSA-6811454 (Reactome)
ADPArrowR-HSA-8857925 (Reactome)
ADPArrowR-HSA-8948757 (Reactome)
AKT inhibitors:AKTArrowR-HSA-2400010 (Reactome)
AKT inhibitorsR-HSA-2400010 (Reactome)
AKT/AKT1 E17K mutantR-HSA-2400010 (Reactome)
AKT1 E17K mutant:PIP2ArrowR-HSA-2219536 (Reactome)
AKT1 E17K mutant:PIP2R-HSA-2243938 (Reactome)
AKT1 E17KR-HSA-2219536 (Reactome)
AKT1ArrowR-HSA-6811504 (Reactome)
AKT1S1R-HSA-200143 (Reactome)
AKT:PIP3:THEM4/TRIB3ArrowR-HSA-199443 (Reactome)
AKT:PIP3:THEM4/TRIB3TBarR-HSA-198640 (Reactome)
AKT:PIP3ArrowR-HSA-2317332 (Reactome)
AKT:PIP3R-HSA-198640 (Reactome)
AKT:PIP3R-HSA-199443 (Reactome)
AKTR-HSA-2317332 (Reactome)
ATPR-HSA-1675776 (Reactome)
ATPR-HSA-1676082 (Reactome)
ATPR-HSA-198270 (Reactome)
ATPR-HSA-198347 (Reactome)
ATPR-HSA-198371 (Reactome)
ATPR-HSA-198599 (Reactome)
ATPR-HSA-198609 (Reactome)
ATPR-HSA-198611 (Reactome)
ATPR-HSA-198613 (Reactome)
ATPR-HSA-198621 (Reactome)
ATPR-HSA-198640 (Reactome)
ATPR-HSA-199298 (Reactome)
ATPR-HSA-199299 (Reactome)
ATPR-HSA-199839 (Reactome)
ATPR-HSA-199863 (Reactome)
ATPR-HSA-200143 (Reactome)
ATPR-HSA-2243938 (Reactome)
ATPR-HSA-2243942 (Reactome)
ATPR-HSA-2316434 (Reactome)
ATPR-HSA-6811454 (Reactome)
ATPR-HSA-8857925 (Reactome)
ATPR-HSA-8948757 (Reactome)
Activated SRC,LCK,EGFR,INSRmim-catalysisR-HSA-8857925 (Reactome)
Activator:PI3Kmim-catalysisR-HSA-2316434 (Reactome)
Active AKTArrowR-HSA-198270 (Reactome)
Active AKTArrowR-HSA-198298 (Reactome)
Active AKTR-HSA-198298 (Reactome)
Active AKTR-HSA-199425 (Reactome)
Active AKTmim-catalysisR-HSA-198347 (Reactome)
Active AKTmim-catalysisR-HSA-198371 (Reactome)
Active AKTmim-catalysisR-HSA-198599 (Reactome)
Active AKTmim-catalysisR-HSA-198609 (Reactome)
Active AKTmim-catalysisR-HSA-198611 (Reactome)
Active AKTmim-catalysisR-HSA-198613 (Reactome)
Active AKTmim-catalysisR-HSA-198621 (Reactome)
Active AKTmim-catalysisR-HSA-199298 (Reactome)
Active AKTmim-catalysisR-HSA-199299 (Reactome)
Active AKTmim-catalysisR-HSA-199839 (Reactome)
Active AKTmim-catalysisR-HSA-199863 (Reactome)
Active AKTmim-catalysisR-HSA-200143 (Reactome)
Active AKTmim-catalysisR-HSA-8948757 (Reactome)
BADR-HSA-198347 (Reactome)
CASP9(1-416)R-HSA-198621 (Reactome)
CDKN1A,CDKN1BR-HSA-198613 (Reactome)
CHUKR-HSA-198611 (Reactome)
CREB1R-HSA-199298 (Reactome)
FOXO1,FOXO3,FOXO4R-HSA-199299 (Reactome)
GSK3R-HSA-198371 (Reactome)
H2OR-HSA-199425 (Reactome)
H2OR-HSA-199456 (Reactome)
H2OR-HSA-6811504 (Reactome)
IER3ArrowR-HSA-6811454 (Reactome)
IER3R-HSA-6811472 (Reactome)
IL33:IL1RL1:IL1RAP-1:MYD88:IRAK1,IRAK4,TRAF6ArrowR-HSA-2316434 (Reactome)
MDM2R-HSA-198599 (Reactome)
MKRN1R-HSA-8948757 (Reactome)
NR4A1R-HSA-199863 (Reactome)
PDPK1:PIP2ArrowR-HSA-2219524 (Reactome)
PDPK1:PIP2ArrowR-HSA-2243942 (Reactome)
PDPK1:PIP2R-HSA-2243937 (Reactome)
PDPK1:PIP3ArrowR-HSA-198270 (Reactome)
PDPK1:PIP3ArrowR-HSA-2316429 (Reactome)
PDPK1:PIP3R-HSA-2317314 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2ArrowR-HSA-2243937 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2R-HSA-2243942 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2mim-catalysisR-HSA-2243942 (Reactome)
PDPK1R-HSA-2219524 (Reactome)
PDPK1R-HSA-2316429 (Reactome)
PHLPP (Mn2+ cofactor)mim-catalysisR-HSA-199425 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2316434 (Reactome)
PI(3,4,5)P3R-HSA-199456 (Reactome)
PI(3,4,5)P3R-HSA-2316429 (Reactome)
PI(3,4,5)P3R-HSA-2317332 (Reactome)
PI(4,5)P2ArrowR-HSA-1675776 (Reactome)
PI(4,5)P2ArrowR-HSA-1676082 (Reactome)
PI(4,5)P2ArrowR-HSA-199456 (Reactome)
PI(4,5)P2R-HSA-2219524 (Reactome)
PI(4,5)P2R-HSA-2219536 (Reactome)
PI(4,5)P2R-HSA-2316434 (Reactome)
PI3K mutants,Activator:PI3KR-HSA-2400009 (Reactome)
PI3K Inhibitors:PI3KArrowR-HSA-2400009 (Reactome)
PI3K inhibitorsR-HSA-2400009 (Reactome)
PI4PR-HSA-1676082 (Reactome)
PI5PArrowR-HSA-8857925 (Reactome)
PI5PR-HSA-1675776 (Reactome)
PI5PTBarR-HSA-6811504 (Reactome)
PIP4K2 dimersmim-catalysisR-HSA-1675776 (Reactome)
PIP5K1A-Cmim-catalysisR-HSA-1676082 (Reactome)
PP2A-A:PP2A-CArrowR-HSA-6811454 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersArrowR-HSA-6811472 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersR-HSA-6811454 (Reactome)
PP2A-B56-beta,gamma:IER3:p-T,Y-MAPK dimersmim-catalysisR-HSA-6811454 (Reactome)
PP2A-B56-beta,gammaR-HSA-6811472 (Reactome)
PP2A-B56-beta,gammamim-catalysisR-HSA-6811504 (Reactome)
PP2AR-HSA-8857925 (Reactome)
PTEN geneR-HSA-5632939 (Reactome)
PTEN geneR-HSA-5632993 (Reactome)
PTEN mRNA:miR-26A RISCArrowR-HSA-2318752 (Reactome)
PTEN mRNA:miR-26A RISCTBarR-HSA-2321904 (Reactome)
PTEN mRNAArrowR-HSA-5632993 (Reactome)
PTEN mRNAR-HSA-2318752 (Reactome)
PTEN mRNAR-HSA-2321904 (Reactome)
PTENArrowR-HSA-2321904 (Reactome)
PTENmim-catalysisR-HSA-199456 (Reactome)
PiArrowR-HSA-199425 (Reactome)
PiArrowR-HSA-199456 (Reactome)
PiArrowR-HSA-6811504 (Reactome)
R-HSA-1675776 (Reactome) At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A), beta (PIP4K2B) and gamma (PIP4K2C) homodimers and heterodimers (Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015) phosphorylate phosphatidylinositol 5-phosphate (PI5P) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).

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

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

This reaction is of particular interest because its regulation by small GTPases of the RHO and ARF families, not yet annotated here, ties the process of phosphatidylinositol phosphate biosynthesis to regulation of the actin cytoskeleton and vesicular trafficking, and hence to diverse aspects of cell motility and signalling (Oude Weernink et al. 2004, 2007).
R-HSA-198270 (Reactome) Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-198298 (Reactome) AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A (Borgatti et al. 2003).
R-HSA-198347 (Reactome) Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
R-HSA-198371 (Reactome) GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1.
R-HSA-198599 (Reactome) AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Mayo and Donner 2001, Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of the E3 ubiquitin-protein ligase MDM2 promotes nuclear localization and interferes with the interaction between MDM2 and p14-ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001, Mayo and Donner 2001).
R-HSA-198609 (Reactome) AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a protein complex with TSC1 and this complex acts as a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.
The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
R-HSA-198611 (Reactome) AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival.
R-HSA-198613 (Reactome) Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
R-HSA-198621 (Reactome) AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it.
R-HSA-198640 (Reactome) Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.
Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-199298 (Reactome) AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival.
R-HSA-199299 (Reactome) Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1.
R-HSA-199425 (Reactome) The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT.
R-HSA-199443 (Reactome) The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
R-HSA-199456 (Reactome) At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.
Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999).
R-HSA-199839 (Reactome) Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT.
R-HSA-199863 (Reactome) AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362).
R-HSA-200143 (Reactome) PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004).
R-HSA-2219524 (Reactome) PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999).
R-HSA-2219536 (Reactome) Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008).
R-HSA-2243937 (Reactome) A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473.
R-HSA-2243938 (Reactome) PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008).
R-HSA-2243942 (Reactome) PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999).
R-HSA-2316429 (Reactome) PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
R-HSA-2316434 (Reactome) A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.

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

The MIR26A2 locus is frequently amplified in glioma tumors that retain one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to down-regulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and negatively correlates with the loss of heterozygosity at the PTEN locus in a mouse PTEN +/- glioma model, based on monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
R-HSA-2321904 (Reactome) PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing PTEN protein expression from the remaining allele (Huse et al. 2009). Other microRNAs, which may also be altered in cancer, such as miR-17, miR-19a, miR-19b, miR-20a, miR-20b, miR-21, miR-22, miR-25, miR-93, miR-106a, miR-106b, miR 205, and miR 214, also bind PTEN mRNA and inhibit its translation into protein (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Zhang et al. 2010, Tay et al. 2011, Qu et al. 2012, Cai et al. 2013).
R-HSA-2400009 (Reactome) A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009.
R-HSA-2400010 (Reactome) AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009.
R-HSA-5632939 (Reactome) PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) binds to the p53-binding site at the PTEN promoter level (Stambolic et al. 2001).
R-HSA-5632993 (Reactome) PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) stimulates PTEN transcription (Stambolic et al. 2000, Singh et al. 2002). PTEN, acting as a negative regulator of PI3K/AKT signaling, affects cell survival, cell cycling, proliferation and migration. PTEN regulates TP53 stability by inhibiting AKT-mediated activation of TP53 ubiquitin ligase MDM2, and thus enhances TP53 transcriptional activity and its own transcriptional activation by TP53. Beside their cross-regulation, PTEN and TP53 can interact and cooperate to regulate survival or apoptotic phenomena (Stambolic et al. 2000, Singh et al. 2002, Nakanishi et al. 2014).
In response to UV induced DNA damage, PTEN transcription is stimulated by binding of the transcription factor EGR1 to the promoter region of PTEN (Virolle et al. 2001).
PTEN transcription is also stimulated by binding of the activated nuclear receptor PPARG (PPARgamma) to peroxisome proliferator response elements (PPREs) in the promoter of the PTEN gene (Patel et al. 2001), binding of the ATF2 transcription factor, activated by stress kinases of the p38 MAPK family, to ATF response elements in the PTEN gene promoter (Shen et al. 2006) and by the transcription factor MAF1 (Li et al. 2016).
NR2E1 (TLX) associated with transcription repressors binds the evolutionarily conserved TLX consensus site in the PTEN promoter. NR2E1 inhibits PTEN transcription by associating with various transcriptional repressors, probably in a cell type or tissue specific manner. PTEN transcription is inhibited when NR2E1 forms a complex with ATN1 (atrophin-1) (Zhang et al. 2006, Yokoyama et al. 2008), KDM1A (LSD1) histone methyltransferase containing CoREST complex (Yokoyama et al. 2008), or histone deacetylases HDAC3, HDAC5 or HDAC7 (Sun et al. 2007).
Binding of the transcriptional repressor SNAI1 (Snail1) to the PTEN promoter represses PTEN transcription. SNAI1-mediated repression of PTEN transcription may require phosphorylation of SNAI1 on serine residue S246. Binding of SNAI1 to the PTEN promoter increases in response to ionizing radiation and is implicated in SNAI1-mediated resistance to gamma-radiation induced apoptosis (Escriva et al. 2008). Binding of another Slug/Snail family member SNAI2 (SLUG) to the PTEN gene promoter also represses PTEN transcription (Uygur et al. 2015).
Binding of JUN to the AP-1 element in the PTEN gene promoter (Hettinger et al. 2007) inhibits PTEN transcription. JUN partner FOS is not needed for JUN-mediated downregulation of PTEN (Vasudevan et al. 2007).
Binding of the transcription factor SALL4 to the PTEN gene promoter (Yang et al. 2008) and SALL4-medaited recruitment of the transcriptional repressor complex NuRD (Lu et al. 2009, Gao et al. 2013), containing histone deacetylases HDAC1 and HDAC2, inhibits the PTEN gene transcription. SALL4-mediated recruitment of DNA methyltransferases (DNMTs) is also implicated in transcriptional repression of PTEN (Yang et al. 2012).
Binding of the transcription factor MECOM (EVI1) to the PTEN gene promoter and MECOM-mediated recruitment of polycomb repressor complexes containing BMI1 (supposedly PRC1.4), and EZH2 (PRC2) leads to repression of PTEN transcription (Song et al. 2009, Yoshimi et al. 2011).
R-HSA-6811454 (Reactome) Activated MAPK1 (ERK2) or MAPK3 (ERK1), recruited to the PP2A complex through IER3 (IEX-1), phosphorylate the regulatory subunit PPP2R5B (B56-beta) or PPP2R5C (B56-gamma) of the PP2A complex on serine residue S368 or S337, respectively. ERK-mediated phosphorylation of the PP2A regulatory subunits causes dissociation of the PP2A complex and prevents PP2A-mediated dephosphorylation of AKT1 (Letourneux et al. 2006, Rocher et al. 2007).
R-HSA-6811472 (Reactome) IER3 (IEX-1) recruits both an activated MAPK (MAPK1 (ERK2) or MAPK3 (ERK1)) and the protein phosphatase 2A (PP2A) complex containing regulatory subunits B56-beta (PPP2R5B) or B56-gamma (PPP2R5C), through an interaction with the B56 subunit, forming a tripartite complex (Letourneux et al. 2006, Rocher et al. 2007).
R-HSA-6811504 (Reactome) The protein phosphatase 2A (PP2A) complex containing a regulatory subunit B56 beta (PPP2R5B) or B56 gamma (PPP2R5C) dephosphorylates activated AKT1 on threonine residue T308 and serine residue S473, thus halting PI3K/AKT signaling (Rocher et al. 2007). Phosphatidylinositol-5-phosphate (PI5P) negatively regulates PP2A-mediated dephosphorylation of AKT1 by promoting, through an unknown mechanism, an inhibitory phosphorylation on tyrosine residue Y307 (Chen et al. 1992) of the catalytic subunit of PP2A (Ramel et al. 2009).
R-HSA-8857925 (Reactome) SRC family tyrosine kinases, such as SRC and LCK, as well as receptor tyrosine kinases, such as EGFR and insulin receptor, can phosphorylate the catalytic subunit of serine/threonine protein phosphatase PP2A at tyrosine residue Y307. Phosphorylation at Y307 inhibits the catalytic activity of PP2A. Phosphatidylinositol-5-phosphate (PI5P) positively regulates phosphorylation of the catalytic subunit of PP2A at Y307.
R-HSA-8948757 (Reactome) AKT1 (and possibly AKT2 and AKT3), activated in response to EGF treatment, phosphorylates MKRN1, an E3 ubiquitin ligase, on serine residue S109. AKT-mediated phosphorylation results in stabilization of MKRN1, protecting it from ubiquitination and proteasome-mediated degradation (Lee et al. 2015).
RPS6KB2R-HSA-199839 (Reactome)
THEM4/TRIB3R-HSA-199443 (Reactome)
TORC2 complexmim-catalysisR-HSA-198640 (Reactome)
TORC2 complexmim-catalysisR-HSA-2243938 (Reactome)
TP53 Tetramer:PTEN GeneArrowR-HSA-5632939 (Reactome)
TP53 Tetramer:PTEN GeneArrowR-HSA-5632993 (Reactome)
TP53 TetramerR-HSA-5632939 (Reactome)
TSC2R-HSA-198609 (Reactome)
miR-26A RISCR-HSA-2318752 (Reactome)
p-FOXO1,p-FOXO3,p-FOXO4ArrowR-HSA-199299 (Reactome)
p-S-AKT:PDPK1:PIP3ArrowR-HSA-2317314 (Reactome)
p-S-AKT:PDPK1:PIP3R-HSA-198270 (Reactome)
p-S-AKT:PDPK1:PIP3mim-catalysisR-HSA-198270 (Reactome)
p-S-AKT:PIP3ArrowR-HSA-198640 (Reactome)
p-S-AKT:PIP3R-HSA-2317314 (Reactome)
p-S109-MKRN1ArrowR-HSA-8948757 (Reactome)
p-S133-CREB1ArrowR-HSA-199298 (Reactome)
p-S15,S356-RPS6KB2ArrowR-HSA-199839 (Reactome)
p-S166,S188-MDM2ArrowR-HSA-198599 (Reactome)
p-S183,T246-AKT1S1ArrowR-HSA-200143 (Reactome)
p-S196-CASP9(1-416)ArrowR-HSA-198621 (Reactome)
p-S351-NR4A1ArrowR-HSA-199863 (Reactome)
p-S368-PPP2R5B,p-S337-PPP2R5CArrowR-HSA-6811454 (Reactome)
p-S473-AKT1 E17K mutant:PIP2ArrowR-HSA-2243938 (Reactome)
p-S473-AKT1 E17K mutant:PIP2R-HSA-2243937 (Reactome)
p-S9/21-GSK3ArrowR-HSA-198371 (Reactome)
p-S939,T1462-TSC2ArrowR-HSA-198609 (Reactome)
p-S99-BADArrowR-HSA-198347 (Reactome)
p-T,Y MAPK dimersArrowR-HSA-6811454 (Reactome)
p-T,Y MAPK dimersR-HSA-6811472 (Reactome)
p-T-AKTArrowR-HSA-199425 (Reactome)
p-T-CDKN1A/BArrowR-HSA-198613 (Reactome)
p-T23-CHUKArrowR-HSA-198611 (Reactome)
p-T308,S473-AKT1 E17KArrowR-HSA-2243942 (Reactome)
p-T308,S473-AKT1R-HSA-6811504 (Reactome)
p-Y307-PP2AArrowR-HSA-8857925 (Reactome)
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