Signaling by insulin receptor (Homo sapiens)

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11, 23, 39, 44, 51...33274130, 38, 4733585413, 37, 463335, 502724, 32, 43, 5340, 45225716, 293, 9, 10, 15, 20...21, 2527349, 49332, 331, 19, 2114, 5242, 5513, 37, 4622, 4913, 37, 462794, 122842, 5530, 368activated insulin receptor insulin RhebGDP p-AMPK heterotrimer insulin ATP6V1B trimer p-AMPK alpha CrkIRS-P TSC1TSC2 PI3K-regulatory subunit PIP3AKT2 complex STRAD p-AMPK heterotrimer p-AMPK heterotrimerAMP ATP6V1G dimer PI3K TSC1TSC2 insulin p-SHC insulin AMPK gamma RhebGTP eIF4E4E-BP PI3K-regulatory subunit phospho-IRS endosome lumenInsulin receptor PIP3Phosphorylated PKB complex AMPK alpha activated insulin receptor phospho-insulin receptor Insulin receptor phospho-insulin receptor phospho-SHC activated insulin receptor PI3K-catalytic subunit ATP6V0D GRB2SOSPhospho-SHC insulin GRB2SOS1 MO25 insulininsulin receptor AMPK beta activated insulin receptor phospho-insulin receptor RhebGTP ATP6V0C hexamer insulin PI3K-catalytic subunit RhebGDP phospho-insulin receptor TSC1p-S1387-TSC2 phospho-IRSPI3K GRB2SOS1 PKB regulator ATP6V0A p21 RASGDP p21 RASGTP CrkSOS ATP6V1B ATP6V1 Activated mTORC1 phospho-IRS activated insulin receptor insulin phospho-insulin receptor p-IRS1,2 p-AMPK alpha ATP6V1G SHCactivated insulin receptor GRB2phospho-SHC insulin p-IRS1,2 p-SHC insulin eIF4E4E-BP1-P p21 RAS p-IRS1,2 phospho-insulin receptor p21 RAS LKB1STRADMO25 AMPK gamma GRB2SOSIRS-P IRSactivated insulin receptor GRB2IRS-P p-IRS1,2 phospho-insulin receptor TSC1Inhibited TSC2-1-P AMPK heterotrimer ATP6V0 ATP6V0E GRB10INSR RhebGTP activated insulin receptor CrkSOSIRS-P V-ATPase ATP6V1A trimer ATP6V1E PIP3PDK1 complex ATP6V1C cytosolinsulin PKBPKB Regulator activated insulin receptor AMPK beta insulin receptor activated insulin receptor IRS PI3K phospho-insulin receptor phospho-IRSactivated insulin receptor GRB2SOS1 AMPK gamma AMPK beta INSRCrkIRS-PSHC1GRB2-1 4xHC-INSMLST8 SOS1 SHCactivated insulin receptorCRKDOK1 ADPATP6V0A4 ATPp-S939,S1130,T1462-TSC2 INSATPADPATP2xHC-INSINSp-Y-SHC3 INSMLST8protein tyrosine phosphataseRHEB MTORGTPGDPIRSactivated insulin receptorGDPATP6V1E2 p-Y-SHC1 p-S366-EEF2Kp-Y-DOK1 H2ORPS6ADPPRKAB2 RHEB GRB2-1 p-Y-IRS1 p-SHCATPMTOR PIK3R2 AKT2 PiPIK3R1 EIF4E PRKAB1STRADA p-T37,T46-EIF4EBP1PiADPPRKAG3 ATP6V1B2 p-Y-IRS1 ATPH+p-Y-IRS2 NRAS p-S939,S1130,T1462-TSC24xHC-INSPIP3PDK1 complexp-Y-DOK1 p21 RASGDPATP6V0D2 p-6Y-INSRSOS1 p-Y-IRS2 p21 RASGTPp-Y317-SHC1 GDP KRASADPMAPK3ATPp-Y-IRS2 p-6Y-INSRPRKAA1 p-Y-IRS2 p-4S-SOS1ATP6V0E1 PIP3AKT2 complexp-S722,S792-RPTOR-1p-6Y-INSRADPATPGRB2SOS1PKBPKB RegulatorTSC1TSC2IRSp-AMPK heterotrimerAMPINSPIK3R2 GDP GRB2SOSPhospho-SHC3',5'-Cyclic AMPactivated insulin receptorINSRRhebGDPTSC1Inhibited TSC2-1-PATP6V1E1GRB2phospho-SHCp-Y-IRS1 Activated mTORC1AKT2 TSC1p-S1387-TSC2ATPp-Y-IRS1 PDPK1IDACAB39 p-T37,T46-EIF4EBP1 PRKAG3 EIF4EAMP GTP RPS6KB12xHC-INSATP6V0E2 p-S318-PDE3Bp-Y-SHC2 INSRINSRPIK3CB Insulin receptorINSRPIINSREEF2KTSC1 CrkSOSIRS-PGRB2IRS-PATP6V1G2 p-Y-IRS1 INSRp-Y-IRS1 RHEB HRASPIP3INSRPRKAB1H2OPRKAG1 RhebGTPATP6V1C1 HRASphospho-IRSADPATP6V0B phospho-insulin receptorATPATP6V1G1 ATP6V1C2 PIP3 TSC1TSC2ADPTRIB3 4xHC-INSTSC2 PIP3Phosphorylated PKB complexV-ATPaseIRS1 p-T174-PRKAA1INSRAMPTSC2 p-Y-SHC3 insulininsulin receptorTSC22xHC-INSPKB regulatorp-T172-PRKAA2 ADPp-T174-PRKAA14xHC-INSTHEM4 GRB10INSRRHEB p-AMPK heterotrimerRPTOR GRB2SOSIRS-PAMPK heterotrimerp-6Y-INSRATP6V1F LKB1STRADMO25GRB10PRKAG2 INSRADPp-T172-PRKAA2 Activated PI3KPiMO25GRB2-1 2xHC-INSPiSTK11p-Y-SHC1 PRKAB2 p-S1108,S1148,S1192-EIF4G1PIK3CA p-5S-RPS6PI3KTSC1 STRADB 4xHC-INSRHEB 4xHC-INSATP6V1A AMPEIF4G1p-S422-EIF4BH+RAF/MAP kinase cascadeADPATP6V1G3 insulinATPPRKAG1 STRADGTP INSRSOS1 4xHC-INS4xHC-INSinsulinADPEIF4E ATP6V1B1 eIF4E4E-BP1-PSHC1 ATPPRKAG2 PIP3 2xHC-INSATP6V1H eIF4E4E-BPSTK11CRK2xHC-INSGTP GRB2-1 PIK3CB EIF4EBP1 ATP6V0A1 activated insulin receptorTSC1 INSRPDE3BPRKAA2 ATPp-6Y-INSRATP6V1D ADPPIK3CA ATP6V0A2 PRKAG3 p-6Y-INSRTCIRG1 phospho-IRSPI3KADPATPGTP phospho-SHC activated insulin receptorATPRPTORp-Y317-SHC1ATPp-Y-IRS2 GRB2-1 ATPp-S371,T389-RPS6KB1PIP3 GRB10 insulin receptorTSC1 PDPK1 GTPADPADPRhebGDPADPphospho-IRSactivated insulin receptorINSREIF4Bp-Y-IRS2 ATPINSRPRKAB2 PPM1ASOS1 ATP6V0C p-Y-SHC2 IRS2 KRASPRKAG1 p-6Y-INSRCAB39L ADPp-IRS1,2p-6Y-INSR2xHC-INSNRAS 2xHC-INSp-S1387-TSC2 RhebGTPAKT2 PRKAG2 PIK3R1 PRKAB1ATP6V0D1 ATPGDP AMP6, 1817, 2620, 5724


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Wikipathways-description 
Insulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (e.g. IRS and Shc) by the insulin receptor tyrosine kinase. This allows association of IRSs with downstream effectors such as PI-3K via its Src homology 2 (SH2) domains leading to end point events such as Glut4 translocation. Shc when tyrosine phosphorylated associates with Grb2 and can thus activate the Ras/MAPK pathway independent of the IRSs.

Signal transduction by the insulin receptor is not limited to its activation at the cell surface. The activated ligand-receptor complex initially at the cell surface, is internalised into endosomes itself a process which is dependent on tyrosine autophosphorylation. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allows the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. Acidification of the endosomal lumen, due to the presence of proton pumps, results in dissociation of insulin from its receptor. (The endosome constitutes the major site of insulin degradation). This loss of the ligand-receptor complex attenuates any further insulin-driven receptor re-phosphorylation events and leads to receptor dephosphorylation by extra-lumenal endosomally-associated protein tyrosine phosphatases (PTPs). The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.

Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=74752

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Bibliography

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History

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CompareRevisionActionTimeUserComment
116792view09:59, 14 May 2021EweitzModified title
114858view16:36, 25 January 2021ReactomeTeamReactome version 75
113304view11:37, 2 November 2020ReactomeTeamReactome version 74
112516view15:47, 9 October 2020ReactomeTeamReactome version 73
101428view11:30, 1 November 2018ReactomeTeamreactome version 66
100966view21:08, 31 October 2018ReactomeTeamreactome version 65
100503view19:42, 31 October 2018ReactomeTeamreactome version 64
100049view16:25, 31 October 2018ReactomeTeamreactome version 63
99601view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93880view13:42, 16 August 2017ReactomeTeamreactome version 61
93448view11:23, 9 August 2017ReactomeTeamreactome version 61
86540view09:20, 11 July 2016ReactomeTeamreactome version 56
83205view10:22, 18 November 2015ReactomeTeamVersion54
81585view13:07, 21 August 2015ReactomeTeamVersion53
77046view08:34, 17 July 2014ReactomeTeamFixed remaining interactions
76751view12:11, 16 July 2014ReactomeTeamFixed remaining interactions
76076view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75786view11:31, 10 June 2014ReactomeTeamReactome 48 Update
75136view14:08, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74783view08:52, 30 April 2014ReactomeTeamReactome46
45215view17:26, 7 October 2011KhanspersOntology Term : 'insulin signaling pathway' added !
42129view21:59, 4 March 2011MaintBotAutomatic update
39939view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHC-INSProteinP01308 (Uniprot-TrEMBL)
3',5'-Cyclic AMPMetaboliteCHEBI:17489 (ChEBI)
4xHC-INSProteinP01308 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT2 ProteinP31751 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
AMPK heterotrimerComplexREACT_18135 (Reactome)
ATP6V0A1 ProteinQ93050 (Uniprot-TrEMBL)
ATP6V0A2 ProteinQ9Y487 (Uniprot-TrEMBL)
ATP6V0A4 ProteinQ9HBG4 (Uniprot-TrEMBL)
ATP6V0B ProteinQ99437 (Uniprot-TrEMBL)
ATP6V0C ProteinP27449 (Uniprot-TrEMBL)
ATP6V0D1 ProteinP61421 (Uniprot-TrEMBL)
ATP6V0D2 ProteinQ8N8Y2 (Uniprot-TrEMBL)
ATP6V0E1 ProteinO15342 (Uniprot-TrEMBL)
ATP6V0E2 ProteinQ8NHE4 (Uniprot-TrEMBL)
ATP6V1A ProteinP38606 (Uniprot-TrEMBL)
ATP6V1B1 ProteinP15313 (Uniprot-TrEMBL)
ATP6V1B2 ProteinP21281 (Uniprot-TrEMBL)
ATP6V1C1 ProteinP21283 (Uniprot-TrEMBL)
ATP6V1C2 ProteinQ8NEY4 (Uniprot-TrEMBL)
ATP6V1D ProteinQ9Y5K8 (Uniprot-TrEMBL)
ATP6V1E1ProteinP36543 (Uniprot-TrEMBL)
ATP6V1E2 ProteinQ96A05 (Uniprot-TrEMBL)
ATP6V1F ProteinQ16864 (Uniprot-TrEMBL)
ATP6V1G1 ProteinO75348 (Uniprot-TrEMBL)
ATP6V1G2 ProteinO95670 (Uniprot-TrEMBL)
ATP6V1G3 ProteinQ96LB4 (Uniprot-TrEMBL)
ATP6V1H ProteinQ9UI12 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated PI3KREACT_9165 (Reactome)
Activated mTORC1ComplexREACT_7770 (Reactome)
CAB39 ProteinQ9Y376 (Uniprot-TrEMBL)
CAB39L ProteinQ9H9S4 (Uniprot-TrEMBL)
CRKProteinP46108 (Uniprot-TrEMBL)
Crk IRS-PComplexREACT_4822 (Reactome)
Crk

SOS

IRS-P
ComplexREACT_2957 (Reactome)
DOK1 ProteinQ99704 (Uniprot-TrEMBL)
EEF2KProteinO00418 (Uniprot-TrEMBL)
EIF4BProteinP23588 (Uniprot-TrEMBL)
EIF4E ProteinP06730 (Uniprot-TrEMBL)
EIF4EBP1 ProteinQ13541 (Uniprot-TrEMBL)
EIF4EProteinP06730 (Uniprot-TrEMBL)
EIF4G1ProteinQ04637 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB10 INSRComplexREACT_5054 (Reactome)
GRB10 ProteinQ13322 (Uniprot-TrEMBL)
GRB10ProteinQ13322 (Uniprot-TrEMBL)
GRB2 IRS-PComplexREACT_5160 (Reactome)
GRB2

SOS

IRS-P
ComplexREACT_3414 (Reactome)
GRB2

SOS

Phospho-SHC
ComplexREACT_2380 (Reactome)
GRB2 SOS1ComplexREACT_4435 (Reactome)
GRB2 phospho-SHCComplexREACT_2584 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRASProteinP01112 (Uniprot-TrEMBL)
IDAREACT_2385 (Reactome)
INSProteinP01308 (Uniprot-TrEMBL)
INSRProteinP06213 (Uniprot-TrEMBL)
IRS activated insulin receptorComplexREACT_3393 (Reactome)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
IRSProteinREACT_2507 (Reactome) The proteins mentioned here are examples of IRS family members acting as indicated for IRS. More family members are to be confirmed and added in the future.
Insulin receptorComplexREACT_5691 (Reactome) The human insulin receptor is expressed as two isoforms that are generated by alternate splicing of its mRNA; the B isoform has 12 additional amino acids (718-729) encoded by exon 11 of the gene.
KRASProteinP01116 (Uniprot-TrEMBL)
LKB1

STRAD

MO25
ComplexREACT_17994 (Reactome)
MAPK3ProteinP27361 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MLST8ProteinQ9BVC4 (Uniprot-TrEMBL)
MO25ProteinREACT_17734 (Reactome)
MTOR ProteinP42345 (Uniprot-TrEMBL)
MTORProteinP42345 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PDE3BProteinQ13370 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI3KComplexREACT_4240 (Reactome)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIP3 AKT2 complexComplexREACT_4871 (Reactome)
PIP3 PDK1 complexComplexREACT_5409 (Reactome)
PIP3 Phosphorylated PKB complexComplexREACT_3373 (Reactome)
PIP3 MetaboliteCHEBI:16618 (ChEBI)
PIP3CHEBI:16618 (ChEBI)
PKB PKB RegulatorComplexREACT_4747 (Reactome)
PKB regulatorProteinREACT_5778 (Reactome)
PPM1AProteinP35813 (Uniprot-TrEMBL)
PRKAA1 ProteinQ13131 (Uniprot-TrEMBL)
PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
PRKAB1ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF/MAP kinase cascadePathwayREACT_634 (Reactome) The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
RHEB ProteinQ15382 (Uniprot-TrEMBL)
RPS6KB1ProteinP23443 (Uniprot-TrEMBL)
RPS6ProteinP62753 (Uniprot-TrEMBL)
RPTOR ProteinQ8N122 (Uniprot-TrEMBL)
RPTORProteinQ8N122 (Uniprot-TrEMBL)
Rheb GDPComplexREACT_7464 (Reactome)
Rheb GTPComplexREACT_7765 (Reactome)
SHC activated insulin receptorComplexREACT_3791 (Reactome)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STK11ProteinQ15831 (Uniprot-TrEMBL)
STRADA ProteinQ7RTN6 (Uniprot-TrEMBL)
STRADB ProteinQ9C0K7 (Uniprot-TrEMBL)
STRADProteinREACT_17339 (Reactome)
TCIRG1 ProteinQ13488 (Uniprot-TrEMBL)
THEM4 ProteinQ5T1C6 (Uniprot-TrEMBL)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
TSC1 Inhibited TSC2-1-PComplexREACT_7650 (Reactome)
TSC1 TSC2ComplexREACT_7850 (Reactome)
TSC1 p-S1387-TSC2ComplexREACT_21675 (Reactome)
TSC1 ProteinQ92574 (Uniprot-TrEMBL)
TSC2 ProteinP49815 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
V-ATPaseComplexREACT_24332 (Reactome)
activated insulin receptorComplexREACT_3057 (Reactome)
activated insulin receptorComplexREACT_4836 (Reactome)
eIF4E 4E-BP1-PComplexREACT_7838 (Reactome)
eIF4E 4E-BPComplexREACT_3978 (Reactome)
insulin insulin receptorComplexREACT_3518 (Reactome)
insulin receptorComplexREACT_3854 (Reactome)
insulinComplexREACT_3655 (Reactome)
insulinComplexREACT_5828 (Reactome)
p-4S-SOS1ProteinQ07889 (Uniprot-TrEMBL)
p-5S-RPS6ProteinP62753 (Uniprot-TrEMBL)
p-6Y-INSRProteinP06213 (Uniprot-TrEMBL)
p-AMPK heterotrimer AMPComplexREACT_21851 (Reactome)
p-AMPK heterotrimerComplexREACT_17720 (Reactome)
p-IRS1,2ProteinREACT_4523 (Reactome)
p-S1108,S1148,S1192-EIF4G1ProteinQ04637 (Uniprot-TrEMBL)
p-S1387-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S318-PDE3BProteinQ13370 (Uniprot-TrEMBL)
p-S366-EEF2KProteinO00418 (Uniprot-TrEMBL)
p-S371,T389-RPS6KB1ProteinP23443 (Uniprot-TrEMBL)
p-S422-EIF4BProteinP23588 (Uniprot-TrEMBL)
p-S722,S792-RPTOR-1ProteinQ8N122-1 (Uniprot-TrEMBL)
p-S939,S1130,T1462-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S939,S1130,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-SHCProteinREACT_12146 (Reactome)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T174-PRKAA1ProteinQ13131 (Uniprot-TrEMBL)
p-T37,T46-EIF4EBP1 ProteinQ13541 (Uniprot-TrEMBL)
p-T37,T46-EIF4EBP1ProteinQ13541 (Uniprot-TrEMBL)
p-Y-DOK1 ProteinQ99704 (Uniprot-TrEMBL)
p-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y-SHC2 ProteinP98077 (Uniprot-TrEMBL)
p-Y-SHC3 ProteinQ92529 (Uniprot-TrEMBL)
p-Y317-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y317-SHC1ProteinP29353 (Uniprot-TrEMBL)
p21 RAS GDPComplexREACT_2657 (Reactome)
p21 RAS GTPComplexREACT_4782 (Reactome)
phospho-IRS PI3KComplexREACT_3175 (Reactome)
phospho-IRS activated insulin receptorComplexREACT_4013 (Reactome)
phospho-IRSProteinREACT_4422 (Reactome)
phospho-SHC activated insulin receptorComplexREACT_4738 (Reactome)
phospho-insulin receptorComplexREACT_3809 (Reactome)
protein tyrosine phosphataseREACT_3980 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3',5'-Cyclic AMPREACT_325 (Reactome)
ADPArrowREACT_11183 (Reactome)
ADPArrowREACT_1420 (Reactome)
ADPArrowREACT_169 (Reactome)
ADPArrowREACT_1878 (Reactome)
ADPArrowREACT_2015 (Reactome)
ADPArrowREACT_21348 (Reactome)
ADPArrowREACT_21413 (Reactome)
ADPArrowREACT_2211 (Reactome)
ADPArrowREACT_244 (Reactome)
ADPArrowREACT_26 (Reactome)
ADPArrowREACT_342 (Reactome)
ADPArrowREACT_6725 (Reactome)
ADPArrowREACT_6778 (Reactome)
ADPArrowREACT_6870 (Reactome)
ADPArrowREACT_6873 (Reactome)
ADPArrowREACT_6883 (Reactome)
ADPArrowREACT_6912 (Reactome)
ADPArrowREACT_6948 (Reactome)
ADPArrowREACT_6952 (Reactome)
ADPArrowREACT_908 (Reactome)
AMPArrowREACT_11183 (Reactome)
AMPK heterotrimerArrowREACT_21418 (Reactome)
AMPK heterotrimerREACT_11183 (Reactome)
AMPREACT_21293 (Reactome)
ATPREACT_11183 (Reactome)
ATPREACT_1420 (Reactome)
ATPREACT_169 (Reactome)
ATPREACT_1878 (Reactome)
ATPREACT_2015 (Reactome)
ATPREACT_21348 (Reactome)
ATPREACT_21413 (Reactome)
ATPREACT_2211 (Reactome)
ATPREACT_244 (Reactome)
ATPREACT_26 (Reactome)
ATPREACT_342 (Reactome)
ATPREACT_6725 (Reactome)
ATPREACT_6778 (Reactome)
ATPREACT_6870 (Reactome)
ATPREACT_6873 (Reactome)
ATPREACT_6883 (Reactome)
ATPREACT_6912 (Reactome)
ATPREACT_6948 (Reactome)
ATPREACT_6952 (Reactome)
ATPREACT_908 (Reactome)
ATPTBarREACT_11183 (Reactome)
Activated PI3Kmim-catalysisREACT_244 (Reactome)
Activated mTORC1mim-catalysisREACT_6873 (Reactome)
Activated mTORC1mim-catalysisREACT_6948 (Reactome)
Crk IRS-PArrowREACT_26 (Reactome)
Crk

SOS

IRS-P
REACT_26 (Reactome)
EEF2KREACT_6883 (Reactome)
EIF4BREACT_6778 (Reactome)
EIF4EArrowREACT_6742 (Reactome)
EIF4G1REACT_6870 (Reactome)
GDPArrowREACT_1672 (Reactome)
GDPArrowREACT_2010 (Reactome)
GDPArrowREACT_6895 (Reactome)
GRB10REACT_509 (Reactome)
GRB2 IRS-PArrowREACT_169 (Reactome)
GRB2

SOS

IRS-P
REACT_169 (Reactome)
GRB2

SOS

IRS-P
mim-catalysisREACT_1672 (Reactome)
GRB2

SOS

Phospho-SHC
REACT_1420 (Reactome)
GRB2

SOS

Phospho-SHC
mim-catalysisREACT_2010 (Reactome)
GRB2 SOS1REACT_176 (Reactome)
GRB2 SOS1REACT_646 (Reactome)
GRB2 phospho-SHCArrowREACT_1420 (Reactome)
GTPREACT_1672 (Reactome)
GTPREACT_2010 (Reactome)
GTPREACT_6895 (Reactome)
H2OREACT_21418 (Reactome)
H2OREACT_325 (Reactome)
IDAmim-catalysisREACT_1355 (Reactome)
IRS activated insulin receptorREACT_342 (Reactome)
IRS activated insulin receptormim-catalysisREACT_342 (Reactome)
IRSArrowREACT_1810 (Reactome)
IRSREACT_2120 (Reactome)
Insulin receptorREACT_1459 (Reactome)
LKB1

STRAD

MO25
mim-catalysisREACT_11183 (Reactome)
MAPK3mim-catalysisREACT_1420 (Reactome)
MAPK3mim-catalysisREACT_169 (Reactome)
MAPK3mim-catalysisREACT_26 (Reactome)
MLST8REACT_6851 (Reactome)
MO25REACT_21345 (Reactome)
MTORREACT_6851 (Reactome)
PDE3BREACT_1878 (Reactome)
PDPK1REACT_260 (Reactome)
PI3KREACT_537 (Reactome)
PIP3 AKT2 complexArrowREACT_1622 (Reactome)
PIP3 AKT2 complexREACT_908 (Reactome)
PIP3 PDK1 complexmim-catalysisREACT_908 (Reactome)
PIP3 Phosphorylated PKB complexArrowREACT_908 (Reactome)
PIP3 Phosphorylated PKB complexmim-catalysisREACT_1878 (Reactome)
PIP3 Phosphorylated PKB complexmim-catalysisREACT_6725 (Reactome)
PIP3 Phosphorylated PKB complexmim-catalysisREACT_6952 (Reactome)
PIP3ArrowREACT_244 (Reactome)
PIP3REACT_1622 (Reactome)
PIP3REACT_260 (Reactome)
PIREACT_244 (Reactome)
PKB PKB RegulatorREACT_1622 (Reactome)
PKB regulatorArrowREACT_1622 (Reactome)
PPM1Amim-catalysisREACT_21418 (Reactome)
PiArrowREACT_1411 (Reactome)
PiArrowREACT_1810 (Reactome)
PiArrowREACT_21261 (Reactome)
PiArrowREACT_21418 (Reactome)
PiArrowREACT_453 (Reactome)
REACT_106 (Reactome) At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'SHC transforming protein' are present. At the end of this reaction, 1 molecule of 'SHC:activated insulin receptor' is present.

This reaction takes place on the 'internal side of plasma membrane'.

REACT_11183 (Reactome) The cytosolic AMPK complex is activated by phosphorylation. LKB1 phosphorylates AMPK heterotrimer on Thr174 of the alpha 1 subunit (or Thr172 on alpha 2 subunit) leading to activation of AMPK (if cellular AMP/ATP ratio is high) (Hawley SA et al, 2003; Woods A et al, 2003; Shaw RJ et al, 2004). Signals leading to this phosphorylation event can be mediated by exercise, leptin and adiponectin, the hypothalamic-sympathetic nervous system (SNS), and alpha adrenergic receptors, as demonstrated in studies of rat and human skeletal muscle (Minoksohi et al, 2002, Kahn et al, 2005). The details of AMPK activation in response to these stimuli will be annotated in the future. Nuclear AMPK may well be a substrate for LKB1 but, to date, there is no clear evidence for this.
REACT_134 (Reactome) As the endosomal lumen acidifies the insulin dissociates from the insulin receptor making it available for degradation by the insulin degrading activity (IDA) present in the endosomal membrane.
REACT_1355 (Reactome) At the beginning of this reaction, 1 molecule of 'insulin' is present.

This reaction takes place in the 'endosome' and is mediated by the 'insulysin activity of IDA (insulin degrading activity' of 'IDA (insulin degrading activity)'.

REACT_1411 (Reactome) At the beginning of this reaction, 1 molecule of 'phospho-SHC' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'SHC transforming protein' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.

REACT_1420 (Reactome) At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'GRB2:SOS:SHC-P' are present. At the end of this reaction, 1 molecule of 'GRB2:SHC-P', 1 molecule of 'phospho-SOS', and 1 molecule of 'ADP' are present.

This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.

REACT_1459 (Reactome) Under normal physiological conditions blood glucose levels are kept under tight control by a series of regulated steps that ensure glucose homeostasis. Upon feeding glucose levels rise and in response to this the body secretes insulin from pancreatic beta-cells into the blood. At physiological concentrations insulin is present in the blood in its monomeric form. Binding of insulin to its receptor occurs on the receptor alpha-subunits. There are two binding domains involved on the receptor (L1 and L2) and it is thought that the amino-terminus of insulin binds with L1 on one of the alpha-subunits and the carboxyterminus with L2 on the other alpha-subunit.

The binding of insulin to its receptor causes a conformational change in the alpha-subunits. This in turn produces a conformational change in the beta-subunits leading to the activation of the intrinsic insulin receptor tyrosine kinase.

REACT_1622 (Reactome) At the beginning of this reaction, 1 molecule of 'PKB:PKB Regulator', and 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate' are present. At the end of this reaction, 1 molecule of 'PKB regulator', and 1 molecule of 'PIP3:PKB complex ' are present.

This reaction takes place in the 'cell'.

REACT_1672 (Reactome) SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.

REACT_169 (Reactome) At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'GRB2:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'GRB2:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.

This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.

REACT_176 (Reactome) Tyrosine receptor kinase stimulation phosphorylates Shc which recruits the SH2 domain of the adaptor protein GRB2, which is complexed with SOS, an exchange factor for p21ras and RAC, through its SH3 domain. Besides SOS, the GRB2 SH3 domain can associate with other intracellular targets, including GAB1. Erk and Rsk mediated phosphorylation results in dissociation of the SOS-GRB2 complex. This may explain why Erk activation through Shc and SOS-GRB2 is transient. Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue. As Shc is phosphorylated by the the stimulated receptor near to the plasma membrane, the SOS-GRB2:Shc interaction brings the SOS enzyme into close proximity to p21ras.
REACT_1810 (Reactome) At the beginning of this reaction, 1 molecule of 'phospho-IRS' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'IRS' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.

REACT_1878 (Reactome) At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'PDE3B' are present. At the end of this reaction, 1 molecule of 'Phosphorylated PDE3B', and 2 molecules of 'ADP' are present.

This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.

REACT_2002 (Reactome) The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. The net effect of this is to lower the pH of the lumen from pH 7.4 (the pH at the plasma membrane) to pH 6.0 (documented with studies using FITC-labeled insulin - a pH dependent fluorescence marker).
REACT_2010 (Reactome) SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.

REACT_2015 (Reactome) At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'SHC:activated insulin receptor' are present. At the end of this reaction, 1 molecule of 'phospho-SHC: activated insulin receptor', and 1 molecule of 'ADP' are present.

This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'SHC:activated insulin receptor'.

REACT_2120 (Reactome) At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'IRS' are present. At the end of this reaction, 1 molecule of 'IRS:activated insulin receptor' is present.

This reaction takes place on the 'internal side of plasma membrane'.

REACT_21261 (Reactome) TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of a small G-protein Rheb. This results in the conversion of Rheb-GTP into Rheb-GDP and in the inhibition of the mTOR activation by GTP-bound Rheb (Inoki K et al, 2003; Tee AR et al, 2003).
REACT_21293 (Reactome) If AMP:ATP ratio rises, AMP (instead of ATP) is bound by the AMPK-gamma subunit, which inhibits the dephosphorylation of the AMPK-alpha subunit resulting in activation of AMPK. It is not clear, as of yet, whether AMP binds to unphosphorylated AMPK.
REACT_21345 (Reactome) Upon complex formation with STRAD and MO25, LKB1 (also known as serine/threonine kinase 11, STK11) is mostly cytosolic. LKB1 attains 20x activity towards the substrates belonging to the subfamily of AMPK-like kinases (5'AMP-activated protein kinases).
REACT_21348 (Reactome) Activated AMPK (phosphorylated on the alpha subunit and AMP bound) phosphorylates TSC2 on Ser1387, thereby activating the GAP activity of the TSC complex via an unknown mechanism.
REACT_21413 (Reactome) Activated AMPK (phosphorylated on Thr172/Thr174 and AMP bound) phosphorylates Raptor on Ser 722 and Ser 792. These phosphorylations are required for inhibition of mTORC1 activity in response to energy stress (Gwinn DM et al, 2008).
REACT_21418 (Reactome) Normally under low AMP:ATP conditions, the active AMPK is dephosphorylated (possibly by PP2C), and thus inactivated.
REACT_2211 (Reactome) For the receptor to autophosphorylate requires a lysine at position 1030 to stabilize the gamma phosphate of ATP whilst the adenosine of ATP itself interacts with three glycines at residues 1003 - 1008. The first tyrosine residues to be autophosphorylated are 1158, 1162 and 1163 in the tyrosine kinase domain. This is shortly followed by tyrosine 972 in the juxtamembrane domain and tyrosines 1328 and 1330. These tyrosines fall into the three distinct tyrosine phosphorylation domains of the beta-subunit. In total there are 13 potential tyrosines that may be phosphorylated. The receptor phosphorylates itself in a trans rather than cis manner. That is one beta-subunit of the receptor phosphorylates the other rather than itself.
REACT_244 (Reactome) At the beginning of this reaction, 1 molecule of 'Phosphatidyl-myo-inositol 4,5-bisphosphate', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate', and 1 molecule of 'ADP' are present.

This reaction takes place in the 'cell' and is mediated by the 'kinase activity' of 'phospho-IRS:PI3K'.

REACT_260 (Reactome) At the beginning of this reaction, 1 molecule of '3-phosphoinositide dependent protein kinase-1 ', and 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate' are present. At the end of this reaction, 1 molecule of 'PIP3:PDK complex [plasma membrane]' is present.

This reaction takes place in the 'cell'.

REACT_26 (Reactome) At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'Crk:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'Crk:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.

This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.

REACT_325 (Reactome) At the beginning of this reaction, 1 molecule of '3',5'-Cyclic AMP' is present. At the end of this reaction, 1 molecule of 'AMP' is present.

This reaction is mediated by the 'hydrolase activity' of 'Phosphorylated PDE3B'.

REACT_342 (Reactome) At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'IRS:activated insulin receptor' are present. At the end of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor', and 1 molecule of 'ADP' are present.

This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'IRS:activated insulin receptor'.

REACT_453 (Reactome) With insulin dissociated from its receptor the signal to sustain the receptor kinase's activity is also removed. Thus endosomally-associated protein tyrosine phosphatases (PTPs) are able to dephosphorylate the receptor which now can not rephosphorylate themselves since insulin is removed and the receptor is in the inactive protein conformation. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)

The dephosphorylation of the receptor is also a signal for the receptor to recycle back to the plasma membrane.

REACT_490 (Reactome) The endosome fuses with the plasma membrane allowing the insulin receptor to re-integrate there. Any degraded insulin remnants which remained in the endosome are also expelled (The majority having been excreted into the cytoplasm and secreted out of the cell via other mechanisms).

The cycle is complete with the dephosphorylated receptor now back in the plasma membrane available to bind the next insulin molecule presented to it. There is some insulin receptor degradation over time when damaged insulin receptors are not recycled but fuse instead with the lysosomes where they are degraded. However the majority of insulin receptors are recycled back to the plasma membrane with greater than 95% efficiency.

REACT_509 (Reactome) At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'GRB10' are present. At the end of this reaction, 1 molecule of 'GRB10:INSR' is present.

This reaction takes place on the 'internal side of plasma membrane'.

REACT_537 (Reactome) IRS1, IRS2 and IRS3 are all known to bind the regulatory subunit of PI3K via its SH2 domain, an interaction that itself activates the kinase activity of the PI3K catalytic subunit.
REACT_562 (Reactome) At the beginning of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'phospho-IRS' are present.

This reaction takes place on the 'internal side of plasma membrane'.

REACT_596 (Reactome) At the beginning of this reaction, 1 molecule of 'phospho-SHC: activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'phospho-SHC', and 1 molecule of 'activated insulin receptor' are present.

This reaction takes place on the 'internal side of plasma membrane'.

REACT_599 (Reactome) Almost concomitantly a second effect resulting from the tyrosine phosphorylation of the insulin receptor begins to occur. The phosphorylation of the tyrosine in the NPEY sequence found in the juxtamembrane is also a signal for endocytosis to occur. Whilst invagination of the plasma membrane commences the receptor tyrosine kinase activity continues unabated as does substrate phosphorylation.

As the invagination continues certain proteins are concentrated in the area of invagination. In addition to the insulin receptor itself there is a recruitment of insulin-specific protein tyrosine phosphatases (PTPs). This process takes less than one minute. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)

The formation of the endosome containing the activated ligand-receptor complex is completed within two minutes following ligand presentation at the plasma membrane and is maximal by five minutes. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allowing the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. The endosome also contains other proteins crucial to the signal transduction process. These include a proton pump and the insulin degrading activity. It is not certain how these proteins arrive in the endosome since it could be via the endosome maturation or fusion pathways.

REACT_646 (Reactome) Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue.
Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues (Y). GRB2 binds the phosphotyrosine residues of IRS via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the SOS-GRB2:IRS interaction brings the SOS enzyme into close proximity to p21ras.
REACT_6725 (Reactome) At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'TSC2-1' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'Inhibited TSC2-1-P at Ser 939, 1130 and Thr 1462' are present.

This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.

REACT_6742 (Reactome) At the beginning of this reaction, 1 molecule of 'eIF4E:4E-BP1-P' is present. At the end of this reaction, 1 molecule of '4E-BP1-P', and 1 molecule of 'eIF4E' are present.

This reaction takes place in the 'cytosol'.

REACT_6778 (Reactome) eIF4B is a physiologically relevant target of S6K1. Once phosphorylated and activated by S6K1, eIF4B specifically stimulates the ATPase and RNA helicase activities of eIF4A.
REACT_6851 (Reactome) mTOR forms a functional protein complex with at least two proteins: Raptor (Regulated Associated Protein of mTOR) and mLst8. This complex is called mammalian TOR complex 1 (mTORC1). Raptor serves as a scaffolding protein to bridge the interaction between mTOR and its substrates. mLst8 enhances the association of mTOR with Raptor. [Rheb:GTP] binds and activates mTORC1. Besides binding directly to mTOR, Rheb can also bind to Raptor and mLst8 (PMIDs 15854902, 15755954 and 12150926).
REACT_6870 (Reactome) At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'eIF4G' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'eIF4G-P' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'kinase activity' of 'S6K1-P'.

REACT_6873 (Reactome) At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'eIF4E:4E-BP' are present. At the end of this reaction, 1 molecule of 'eIF4E:4E-BP1-P', and 2 molecules of 'ADP' are present.

This reaction is mediated by the 'kinase activity' of 'Activated mTORC1'.

REACT_6883 (Reactome) Phosphorylation of eEF2 kinase by S6K1-P results in decreased activity of this kinase. eEF2 kinase normally phosphorylates and deactivates eEF2, preventing its binding to the ribosome.
REACT_6895 (Reactome) Rheb is a GTP binding protein that exhibits GTPase activity. GDP is exchanged for GTP in the [Rheb:GDP] complex to form [Rheb:GTP], which binds and activates the mTORC1 complex. This exchange is catalysed by an as yet unidentified guanine exchange factor (GEF) (PMIDs 15951850 and 15755954).
REACT_6912 (Reactome) Once phosphorylated, S6K1-P phosphorylates and activates ribosomal protein S6 (rpS6), which in turn selectively increases the translation of 5’TOP mRNAs. These mRNAs encode exclusively for components of the translation machinery (PMID 15809305).
REACT_6948 (Reactome) S6K1 contains a TOS motif. mTORC1 requires an intact TOS motif to bind and phosphorylate S6K1 (PMID 15809305).
REACT_6952 (Reactome) At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'TSC1:TSC2' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'TSC1:Inhibited TSC2-1-P' are present.

This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.

REACT_908 (Reactome) At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'PIP3:PKB complex ' are present. At the end of this reaction, 1 molecule of 'PIP3:Phosphorylated PKB complex', and 2 molecules of 'ADP' are present.

This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'PIP3:PDK complex [plasma membrane]'.

RPS6KB1REACT_6948 (Reactome)
RPS6REACT_6912 (Reactome)
RPTORREACT_21413 (Reactome)
RPTORREACT_6851 (Reactome)
Rheb GDPArrowREACT_21261 (Reactome)
Rheb GDPREACT_6895 (Reactome)
Rheb GTPArrowREACT_6895 (Reactome)
Rheb GTPREACT_6851 (Reactome)
SHC activated insulin receptorREACT_2015 (Reactome)
SHC activated insulin receptormim-catalysisREACT_2015 (Reactome)
SHC1ArrowREACT_1411 (Reactome)
SHC1REACT_106 (Reactome)
STK11REACT_21345 (Reactome)
STRADREACT_21345 (Reactome)
TSC1 Inhibited TSC2-1-PArrowREACT_6952 (Reactome)
TSC1 TSC2REACT_21348 (Reactome)
TSC1 TSC2REACT_6952 (Reactome)
TSC1 p-S1387-TSC2ArrowREACT_21348 (Reactome)
TSC1 p-S1387-TSC2mim-catalysisREACT_21261 (Reactome)
TSC2REACT_6725 (Reactome)
V-ATPasemim-catalysisREACT_2002 (Reactome)
activated insulin receptorArrowREACT_2211 (Reactome)
activated insulin receptorArrowREACT_562 (Reactome)
activated insulin receptorArrowREACT_596 (Reactome)
activated insulin receptorREACT_106 (Reactome)
activated insulin receptorREACT_2120 (Reactome)
activated insulin receptorREACT_509 (Reactome)
eIF4E 4E-BP1-PArrowREACT_6873 (Reactome)
eIF4E 4E-BPREACT_6873 (Reactome)
insulin insulin receptorREACT_2211 (Reactome)
insulin insulin receptormim-catalysisREACT_2211 (Reactome)
insulin receptorArrowREACT_453 (Reactome)
insulinArrowREACT_134 (Reactome)
insulinREACT_1459 (Reactome)
p-4S-SOS1ArrowREACT_1420 (Reactome)
p-4S-SOS1ArrowREACT_169 (Reactome)
p-4S-SOS1ArrowREACT_26 (Reactome)
p-5S-RPS6ArrowREACT_6912 (Reactome)
p-AMPK heterotrimer AMPmim-catalysisREACT_21348 (Reactome)
p-AMPK heterotrimer AMPmim-catalysisREACT_21413 (Reactome)
p-AMPK heterotrimerArrowREACT_11183 (Reactome)
p-AMPK heterotrimerREACT_21293 (Reactome)
p-AMPK heterotrimerREACT_21418 (Reactome)
p-IRS1,2REACT_646 (Reactome)
p-S1108,S1148,S1192-EIF4G1ArrowREACT_6870 (Reactome)
p-S318-PDE3BArrowREACT_1878 (Reactome)
p-S318-PDE3Bmim-catalysisREACT_325 (Reactome)
p-S366-EEF2KArrowREACT_6883 (Reactome)
p-S371,T389-RPS6KB1ArrowREACT_6948 (Reactome)
p-S371,T389-RPS6KB1mim-catalysisREACT_6778 (Reactome)
p-S371,T389-RPS6KB1mim-catalysisREACT_6870 (Reactome)
p-S371,T389-RPS6KB1mim-catalysisREACT_6883 (Reactome)
p-S371,T389-RPS6KB1mim-catalysisREACT_6912 (Reactome)
p-S422-EIF4BArrowREACT_6778 (Reactome)
p-S722,S792-RPTOR-1ArrowREACT_21413 (Reactome)
p-S722,S792-RPTOR-1TBarREACT_6948 (Reactome)
p-S939,S1130,T1462-TSC2ArrowREACT_6725 (Reactome)
p-SHCREACT_176 (Reactome)
p-T37,T46-EIF4EBP1ArrowREACT_6742 (Reactome)
p-Y317-SHC1ArrowREACT_596 (Reactome)
p21 RAS GDPREACT_1672 (Reactome)
p21 RAS GDPREACT_2010 (Reactome)
p21 RAS GTPArrowREACT_1672 (Reactome)
p21 RAS GTPArrowREACT_2010 (Reactome)
phospho-IRS activated insulin receptorArrowREACT_342 (Reactome)
phospho-IRSArrowREACT_562 (Reactome)
phospho-IRSREACT_537 (Reactome)
phospho-SHC activated insulin receptorArrowREACT_2015 (Reactome)
phospho-insulin receptorArrowREACT_134 (Reactome)
protein tyrosine phosphatasemim-catalysisREACT_1411 (Reactome)
protein tyrosine phosphatasemim-catalysisREACT_1810 (Reactome)
protein tyrosine phosphatasemim-catalysisREACT_453 (Reactome)

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