Signaling by type 1 insulin-like growth factor 1 receptor (IGF1R) (Homo sapiens)

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13, 14, 21, 24, 26...425817, 585819, 47202, 501, 4, 22, 23, 29...1, 7, 16, 22, 27...3451, 5436, 47, 5020209, 11, 29, 31, 32, 43...2012, 36, 52, 60, 64583728, 563, 12, 25, 35, 40...78, 10, 55, 591558PKB regulator[cytosol]FGFR2c-binding FGFs[extracellularregion]IRS1/2/4 [plasmamembrane]Activated FGFR1chomodimer [plasmamembrane]phospho-IRS[cytosol]p-SHC [cytosol]GRB2 and GAB1 boundto activated FGFRand FRS2-alpha[plasma membrane]IGF1/2:p-IGF1R[plasma membrane]Activated FGFR[plasma membrane,extracellularregion]p21 RAS:GDP [plasmamembrane]Rheb:GTP [cytosol]Klotho[extracellularregion, plasmamembrane]phospho-IRS:PI3K[cytosol]autophosphorylatedIGF1R [plasmamembrane]FGFR1b-binding FGFs[extracellularregion]PI3K [cytosol]IGF1R [plasmamembrane]FGFR1c-binding FGFs[extracellularregion]eIF4E:4E-BP[cytosol]autophosphorylatedIGF1R [plasmamembrane]FGFR4-binding FGFs[extracellularregion]IGF1/2:p-IGF1R:SHC1[plasma membrane]IGF1/2:p-IGF1R[plasma membrane]PI3K-regulatorysubunit [cytosol]IGF1/2:p-IGF1R[plasma membrane]Klotho bound toFGF23 [plasmamembrane]PIP3:AKT2 complex[plasma membrane]autophosphorylatedIGF1R [plasmamembrane]Activated FGFR2blong homodimer [plasma membrane]IGF1/2:p-IGF1R[plasma membrane]IGF1/2:p-IGF1R:p-IRS1/2/4[plasma membrane]PI3K-catalyticsubunit [cytosol]IGF1/2 [plasmamembrane]SHC1 [plasmamembrane]ActivatedFGFR:p-FRS2alpha[plasma membrane]IRS1/4 [plasmamembrane]autophosphorylatedIGF1R [plasmamembrane]Activated FGFR1bhomodimer [plasmamembrane]IGF1/2:p-IGF1R:IRS2[plasma membrane]Activated mTORC1[cytosol]IGF1/2:p-IGF1R:p-SHC1[plasma membrane]PIP3:PhosphorylatedPKB complex [plasmamembrane]IGF1/2 [plasmamembrane]Activated FGFR2chomodimer bound toFGF [plasmamembrane]p21 RAS [plasmamembrane]PIP3:PDK1 complex[plasma membrane]IGF1/2:p-IGF1R[plasma membrane]Activated FGFR2clong homodimer [plasma membrane]PI3K class III[cytosol]IGF1/2:p-IGF1R:IRS1/2/4[plasma membrane]Activated FGFR2bhomodimer bound toFGF [plasmamembrane]Activated PI3K[plasma membrane,endosome membrane,cytosol]PI3K [cytosol]IGF1/2 [plasmamembrane]TSC1:TSC2 [cytosol]activated TLR9:PI3Kclass III [endosomemembrane]IGF1/2:p-IGF1R:IRS1/4[plasma membrane]PI3K [cytosol]TSC1:InhibitedTSC2-1-P [cytosol]PI3K-catalyticsubunit [cytosol]Activated FGFR4bound toFGF19:BetaKlotho[plasma membrane]ActivatedFGFR:p-FRS2-alpha:p-SHP2[plasma membrane]GRB2:SOS:Phospho-SHC[cytosol]eIF4E:4E-BP1-P[cytosol]p21 RAS [plasmamembrane]p-SHC1 [plasmamembrane]IGF1/2 [plasmamembrane]IGF1/2:p-IGF1R[plasma membrane]FGFR3b-binding FGFs[extracellularregion]Klotho homodimer[plasma membrane]autophosphorylatedIGF1R [plasmamembrane]autophosphorylatedIGF1R [plasmamembrane]phospho-IRS[cytosol]IGF1R [plasmamembrane]p-IRS1/2/4 [plasmamembrane]fl-TLR9:unmethylatedCpG DNA [endosomemembrane]PKB:PKB Regulator[cytosol]GRB2:SOS:IRS-P[cytosol]IGF1/2 [plasmamembrane]autophosphorylatedIGF1R [plasmamembrane]IGF1/2 [plasmamembrane]GRB2:SOS1 [cytosol]Rheb:GDP [cytosol]p-IRS1,2 [cytosol]Secreted Klothohomodimer[extracellularregion]Activated FGFR2bshort homodimerbound to FGF [plasmamembrane]Activated FGFR3bhomodimer [plasmamembrane]GRB2:SOS1 [cytosol]Activated FGFR4homodimer [plasmamembrane]FGFR2b-binding FGFs[extracellularregion]Activated FGFR1cbound toFGF23:Klotho [plasmamembrane]PI3K-regulatorysubunit [cytosol]IGF1/2 [plasmamembrane]PI3K-regulatorysubunit [cytosol]Activated FGFR boundto PI3K [plasmamembrane]phospho-IRS:PI3K[cytosol]Activated FGFR2cshort homodimerbound to FGF [plasmamembrane]IGF1/2:p-IGF1R[plasma membrane]Activated FGFR3chomodimer [plasmamembrane]FGFR3c-binding FGFs[extracellularregion]Rheb:GTP [cytosol]PI3K-catalyticsubunit [cytosol]IGF1/2:IGF1R [plasmamembrane]GRB2:SOS1 [cytosol]cytosolp21 RAS:GTP [plasmamembrane]Membrane-boundKlotho homodimer[plasma membrane]IGF1/2 [plasmamembrane]ATPGDP [cytosol]IGF2(25-91) [plasmamembrane]phosphorylatedFGFR3c [plasmamembrane]IRS1 [plasmamembrane]ADPPIK3R2 [cytosol]FGF19 [extracellularregion]SHC1-1(156-583)[plasma membrane]p21 RAS:GTPATPp-S318-PDE3BGTP [cytosol]FGF6 [extracellularregion]PIK3R2 [cytosol]GDPPIP3 [plasmamembrane]FGF17-1[extracellularregion]p-T37,T46-EIF4EBP1[cytosol]PDPK1 [plasmamembrane]IGF1 [plasmamembrane]ATPADPp-8Y-FGFR2-5 [plasmamembrane]p-S422-EIF4BTSC1 [cytosol]ADPGRB2-1 [cytosol]IGF1R(31-736)[plasma membrane]PIK3R1 [cytosol]IGF1R(741-1367)[plasma membrane]MLST8Rheb:GDPp-S939,S1130,T1462-TSC2FGF7 [extracellularregion]ATPp21 RAS:GDPGRB2-1 [cytosol]RPTORPIK3CA [cytosol]p-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]p-6Y-IRS1 [plasmamembrane]IGF1R(31-736)[plasma membrane]FGF3 [extracellularregion]ATPATPp-Y-SHC2 [cytosol]p-Y-IRS2 [cytosol]PIK3R1 [cytosol]PIP3IGF2(25-91) [plasmamembrane]Activated PI3KATPADPRHEB [cytosol]p-Y194,Y195,Y272-SHC1-1(156-583)[plasma membrane]HRAS(1-186) [plasmamembrane]p-S722,S792-RPTOR-1SHC1p-5S-RPS6PIP3ATPIGF1R(741-1367)[plasma membrane]PIP3 [plasmamembrane]IGF1/2:p-IGF1RPI3KPIK3CA [cytosol]ADPGRB2-1 [cytosol]IRS4 [plasmamembrane]RHEB [cytosol]phospho-IRSPIP3 [plasmamembrane]IGF2(25-91) [plasmamembrane]TSC1:InhibitedTSC2-1-PPIK3C3 [cytosol]GTPEIF4B(2-118)NRAS [plasmamembrane]TSC2p-Y-DOK1 [cytosol]p-Y-DOK1 [cytosol]PKB regulatorGDPEIF4E [cytosol]3',5'-Cyclic AMPp-S1108,S1148,S1192-EIF4G1p-5Y-FGFR4 [plasmamembrane]SOS1 [cytosol]EIF4G1RPS6FGF20 [extracellularregion]MTOR [cytosol]TSC1:TSC2IRS2p-Y-IRS2 [cytosol]IGF1 [plasmamembrane]EIF4EBP1 [cytosol]IGF1R(31-736)[plasma membrane]IGF2(25-91) [plasmamembrane]PIK3CB [cytosol]ATPp-Y-SHC3 [cytosol]FGF5-1[extracellularregion]FGF9 [extracellularregion]IRS1/4IRS4 [plasmamembrane]p-Y-IRS2 [cytosol]IGF1/2:p-IGF1R:p-IRS1/2/4p-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]IGF1/2p-IRS1,2ADPTHEM4 [cytosol]IGF1 [plasmamembrane]IGF2(25-91) [plasmamembrane]GDP [cytosol]ATPEIF4E [cytosol]FGF10 [extracellularregion]GTPKL-1 [plasmamembrane]IGF1/2:p-IGF1R:IRS1/2/4p-8xY-FGFR2c long[plasma membrane]IRS2 [plasmamembrane]RPTOR [cytosol]MTORGRB2-1 [cytosol]phosphorylatedFGFR3b [plasmamembrane]ATPp-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]FGF2(10-155)[extracellularregion]ADPp-SHCIGF1R(31-736)[plasma membrane]IGF2(25-91) [plasmamembrane]SHC1 [plasmamembrane]IGF1/2:p-IGF1R:SHC1GRB2:SOS:IRS-PIGF2(25-91) [plasmamembrane]GRB2:SOS1IGF1R(31-736)[plasma membrane]PIK3R1 [cytosol]SOS1 [cytosol]H2OPDPK1p-8Y-FGFR2-3 [plasmamembrane]p-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]RAF/MAP kinasecascadep-T37,T46-EIF4EBP1ADPKL-2 [extracellularregion]Energy dependentregulation of mTORby LKB1-AMPKADPSOS1 [cytosol]p-Y-IRS1 [cytosol]AKT2 [cytosol]AKT2 [cytosol]IGF1 [plasmamembrane]IRS1 [plasmamembrane]IGF1 [plasmamembrane]PIK3CB [cytosol]p-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]p-Y239,Y240,Y317-SHC1-2[plasma membrane]eIF4E:4E-BPGTP [cytosol]p-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]IGF1/2:p-IGF1R:p-SHC1IGF1R(31-736)[plasma membrane]IGF2(25-91) [plasmamembrane]eIF4E:4E-BP1-PIGF1 [plasmamembrane]PIK3R4(2-1358)[cytosol]PhosphorylatedFibroblast growthfactor receptor 2bshort [plasmamembrane]FGF1 [extracellularregion]MLST8 [cytosol]ADPATPFGF18 [extracellularregion]FGF23(25-251)[extracellularregion]PIP3:PDK1 complexIGF1/2:p-IGF1R:IRS1/4IGF1RPIP3:AKT2 complexFGF22 [extracellularregion]FGF8-1[extracellularregion]ATPp-S366-EEF2KATPp-Y1161,Y1165,Y1166-IGF1R(741-1367)[plasma membrane]FGF4 [extracellularregion]p-Y-IRS1 [cytosol]ADPPIK3CA [cytosol]p-S371,T389-RPS6KB1IGF1/2:p-IGF1R:IRS2Activated mTORC1PI(4,5)P2p-Y-IRS4 [plasmamembrane]GTP [cytosol]KRAS(1-186) [plasmamembrane]PKB:PKB RegulatorTLR9 [endosomemembrane]p-6Y-FRS2 [plasmamembrane]HRAS(1-186) [plasmamembrane]p-Y-SHC1 [cytosol]IGF1R(31-736)[plasma membrane]AKT2 [cytosol]ADPADPphosphorylatedFGFR1c [plasmamembrane]EIF4ETSC2 [cytosol]p-Y546,Y584-PTPN11[cytosol]RPS6KB1FGF16 [extracellularregion]GRB2:SOS:Phospho-SHCIGF1 [plasmamembrane]PIK3R2 [cytosol]PIP3:PhosphorylatedPKB complexAMPPIK3CB [cytosol]RHEB [cytosol]Rheb:GTPIGF1R(31-736)[plasma membrane]KRAS(1-186) [plasmamembrane]TRIB3 [cytosol]IGF1R(31-736)[plasma membrane]IGF1/2:IGF1REEF2KADPKLB [plasmamembrane]SHC1-2 [plasmamembrane]TSC1 [cytosol]p-Y-IRS2 [plasmamembrane]phospho-IRS:PI3KPDE3BHeparan Sulphate[extracellularregion]p-Y349,Y350,Y427-SHC1[plasma membrane]IGF1 [plasmamembrane]p-Y-IRS1 [cytosol]GAB1 [cytosol]IRS2 [plasmamembrane]p-S939,S1130,T1462-TSC2[cytosol]NRAS [plasmamembrane]30, 44295296, 18, 57541, 4682929, 47


Description

Binding of IGF1 (IGF-I) or IGF2 (IGF-II) to the extracellular alpha peptides of the type 1 insulin-like growth factor receptor (IGF1R) triggers the activation of two major signaling pathways: the SOS-RAS-RAF-MAPK (ERK) pathway and the PI3K-PKB (AKT) pathway (recently reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parella et al. 2010, Annunziata et al. 2011, Siddle et al. 2012, Holzenberger 2012).Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=2404192

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Bibliography

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History

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CompareRevisionActionTimeUserComment
129733view01:45, 22 May 2024EweitzModified title
114848view16:35, 25 January 2021ReactomeTeamReactome version 75
113294view11:36, 2 November 2020ReactomeTeamReactome version 74
112506view15:46, 9 October 2020ReactomeTeamReactome version 73
101418view11:30, 1 November 2018ReactomeTeamreactome version 66
100956view21:06, 31 October 2018ReactomeTeamreactome version 65
100493view19:41, 31 October 2018ReactomeTeamreactome version 64
100038view16:24, 31 October 2018ReactomeTeamreactome version 63
99591view14:58, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99210view12:43, 31 October 2018ReactomeTeamreactome version 62
93994view13:50, 16 August 2017ReactomeTeamreactome version 61
93603view11:28, 9 August 2017ReactomeTeamreactome version 61
87189view08:08, 19 July 2016EgonwOntology Term : 'signaling pathway' added !
86709view09:24, 11 July 2016ReactomeTeamreactome version 56
83075view09:53, 18 November 2015ReactomeTeamVersion54
81398view12:55, 21 August 2015ReactomeTeamVersion53
76867view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76572view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75905view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75605view10:45, 10 June 2014ReactomeTeamReactome 48 Update
74960view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74604view08:39, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
3',5'-Cyclic AMPMetaboliteCHEBI:17489 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT2 [cytosol]ProteinP31751 (Uniprot-TrEMBL)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated PI3KComplexREACT_9165 (Reactome)
Activated mTORC1ComplexREACT_7770 (Reactome)
EEF2KProteinO00418 (Uniprot-TrEMBL)
EIF4B(2-118)ProteinP23588 (Uniprot-TrEMBL)
EIF4E [cytosol]ProteinP06730 (Uniprot-TrEMBL)
EIF4EBP1 [cytosol]ProteinQ13541 (Uniprot-TrEMBL)
EIF4EProteinP06730 (Uniprot-TrEMBL)
EIF4G1ProteinQ04637 (Uniprot-TrEMBL)
Energy dependent

regulation of mTOR

by LKB1-AMPK		PathwayWP2748 (WikiPathways) Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. If the AMP:ATP ratio rises, this activation is maintained and AMPK activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and inhibition of mTOR pathway.
FGF1 [extracellular region]ProteinP05230 (Uniprot-TrEMBL)
FGF10 [extracellular region]ProteinO15520 (Uniprot-TrEMBL)
FGF16 [extracellular region]ProteinO43320 (Uniprot-TrEMBL)
FGF17-1

[extracellular

region]		ProteinO60258-1 (Uniprot-TrEMBL)
FGF18 [extracellular region]ProteinO76093 (Uniprot-TrEMBL)
FGF19 [extracellular region]ProteinO95750 (Uniprot-TrEMBL)
FGF2(10-155)

[extracellular

region]		ProteinP09038 (Uniprot-TrEMBL)
FGF20 [extracellular region]ProteinQ9NP95 (Uniprot-TrEMBL)
FGF22 [extracellular region]ProteinQ9HCT0 (Uniprot-TrEMBL)
FGF23(25-251)

[extracellular

region]		ProteinQ9GZV9 (Uniprot-TrEMBL)
FGF3 [extracellular region]ProteinP11487 (Uniprot-TrEMBL)
FGF4 [extracellular region]ProteinP08620 (Uniprot-TrEMBL)
FGF5-1

[extracellular

region]		ProteinP12034-1 (Uniprot-TrEMBL)
FGF6 [extracellular region]ProteinP10767 (Uniprot-TrEMBL)
FGF7 [extracellular region]ProteinP21781 (Uniprot-TrEMBL)
FGF8-1

[extracellular

region]		ProteinP55075-1 (Uniprot-TrEMBL)
FGF9 [extracellular region]ProteinP31371 (Uniprot-TrEMBL)
GAB1 [cytosol]ProteinQ13480 (Uniprot-TrEMBL)
GDP [cytosol]MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 [cytosol]ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:SOS1ComplexREACT_4435 (Reactome)
GRB2:SOS:IRS-PComplexREACT_3414 (Reactome)
GRB2:SOS:Phospho-SHCComplexREACT_2380 (Reactome)
GTP [cytosol]MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRAS(1-186) [plasma membrane]ProteinP01112 (Uniprot-TrEMBL)
Heparan Sulphate

[extracellular

region]		MetaboliteCHEBI:28815 (ChEBI)
IGF1 [plasma membrane]ProteinP05019 (Uniprot-TrEMBL)
IGF1/2:IGF1RComplexREACT_151821 (Reactome)
IGF1/2:p-IGF1R:IRS1/2/4ComplexREACT_150878 (Reactome)
IGF1/2:p-IGF1R:IRS1/4ComplexREACT_151270 (Reactome)
IGF1/2:p-IGF1R:IRS2ComplexREACT_151257 (Reactome)
IGF1/2:p-IGF1R:SHC1ComplexREACT_151215 (Reactome)
IGF1/2:p-IGF1R:p-IRS1/2/4ComplexREACT_151884 (Reactome)
IGF1/2:p-IGF1R:p-SHC1ComplexREACT_151817 (Reactome)
IGF1/2:p-IGF1RComplexREACT_150608 (Reactome)
IGF1/2ProteinREACT_17556 (Reactome)
IGF1R(31-736) [plasma membrane]ProteinP08069 (Uniprot-TrEMBL)
IGF1R(741-1367) [plasma membrane]ProteinP08069 (Uniprot-TrEMBL)
IGF1RComplexREACT_152174 (Reactome)
IGF2(25-91) [plasma membrane]ProteinP01344 (Uniprot-TrEMBL)
IRS1 [plasma membrane]ProteinP35568 (Uniprot-TrEMBL)
IRS1/4ProteinREACT_150840 (Reactome)
IRS2 [plasma membrane]ProteinQ9Y4H2 (Uniprot-TrEMBL)
IRS2ProteinQ9Y4H2 (Uniprot-TrEMBL)
IRS4 [plasma membrane]ProteinO14654 (Uniprot-TrEMBL)
KL-1 [plasma membrane]ProteinQ9UEF7-1 (Uniprot-TrEMBL)
KL-2 [extracellular region]ProteinQ9UEF7-2 (Uniprot-TrEMBL)
KLB [plasma membrane]ProteinQ86Z14 (Uniprot-TrEMBL)
KRAS(1-186) [plasma membrane]ProteinP01116 (Uniprot-TrEMBL)
MLST8 [cytosol]ProteinQ9BVC4 (Uniprot-TrEMBL)
MLST8ProteinQ9BVC4 (Uniprot-TrEMBL)
MTOR [cytosol]ProteinP42345 (Uniprot-TrEMBL)
MTORProteinP42345 (Uniprot-TrEMBL)
NRAS [plasma membrane]ProteinP01111 (Uniprot-TrEMBL)
PDE3BProteinQ13370 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDPK1 [plasma membrane]ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3KComplexREACT_4240 (Reactome)
PIK3C3 [cytosol]ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3CA [cytosol]ProteinP42336 (Uniprot-TrEMBL)
PIK3CB [cytosol]ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 [cytosol]ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 [cytosol]ProteinO00459 (Uniprot-TrEMBL)
PIK3R4(2-1358) [cytosol]ProteinQ99570 (Uniprot-TrEMBL)
PIP3 [plasma membrane]MetaboliteCHEBI:16618 (ChEBI)
PIP3:AKT2 complexComplexREACT_4871 (Reactome)
PIP3:PDK1 complexComplexREACT_5409 (Reactome)
PIP3:Phosphorylated PKB complexComplexREACT_3373 (Reactome)
PIP3MetaboliteCHEBI:16618 (ChEBI)
PKB regulatorProteinREACT_5778 (Reactome)
PKB:PKB RegulatorComplexREACT_4747 (Reactome)
Phosphorylated

Fibroblast growth factor receptor 2b short [plasma

membrane]		ProteinP21802-18 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayWP2735 (WikiPathways) 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 [cytosol]ProteinQ15382 (Uniprot-TrEMBL)
RPS6KB1ProteinP23443 (Uniprot-TrEMBL)
RPS6ProteinP62753 (Uniprot-TrEMBL)
RPTOR [cytosol]ProteinQ8N122 (Uniprot-TrEMBL)
RPTORProteinQ8N122 (Uniprot-TrEMBL)
Rheb:GDPComplexREACT_7464 (Reactome)
Rheb:GTPComplexREACT_7765 (Reactome)
SHC1 [plasma membrane]ProteinP29353-1 (Uniprot-TrEMBL)
SHC1-1(156-583) [plasma membrane]ProteinP29353-3 (Uniprot-TrEMBL)
SHC1-2 [plasma membrane]ProteinP29353-2 (Uniprot-TrEMBL)
SHC1ProteinREACT_150482 (Reactome)
SOS1 [cytosol]ProteinQ07889 (Uniprot-TrEMBL)
THEM4 [cytosol]ProteinQ5T1C6 (Uniprot-TrEMBL)
TLR9 [endosome membrane]ProteinQ9NR96 (Uniprot-TrEMBL)
TRIB3 [cytosol]ProteinQ96RU7 (Uniprot-TrEMBL)
TSC1 [cytosol]ProteinQ92574 (Uniprot-TrEMBL)
TSC1:Inhibited TSC2-1-PComplexREACT_7650 (Reactome)
TSC1:TSC2ComplexREACT_7850 (Reactome)
TSC2 [cytosol]ProteinP49815 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
eIF4E:4E-BP1-PComplexREACT_7838 (Reactome)
eIF4E:4E-BPComplexREACT_3978 (Reactome)
p-5S-RPS6ProteinP62753 (Uniprot-TrEMBL)
p-5Y-FGFR4 [plasma membrane]ProteinP22455 (Uniprot-TrEMBL)
p-6Y-FRS2 [plasma membrane]ProteinQ8WU20 (Uniprot-TrEMBL)
p-6Y-IRS1 [plasma membrane]ProteinP35568 (Uniprot-TrEMBL)
p-8Y-FGFR2-3 [plasma membrane]ProteinP21802-3 (Uniprot-TrEMBL)
p-8Y-FGFR2-5 [plasma membrane]ProteinP21802-5 (Uniprot-TrEMBL)
p-8xY-FGFR2c long [plasma membrane]ProteinP21802-1 (Uniprot-TrEMBL)
p-IRS1,2ProteinREACT_4523 (Reactome)
p-S1108,S1148,S1192-EIF4G1ProteinQ04637 (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 [cytosol]ProteinP49815 (Uniprot-TrEMBL)
p-S939,S1130,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-SHCProteinREACT_12146 (Reactome)
p-T37,T46-EIF4EBP1 [cytosol]ProteinQ13541 (Uniprot-TrEMBL)
p-T37,T46-EIF4EBP1ProteinQ13541 (Uniprot-TrEMBL)
p-Y-DOK1 [cytosol]ProteinQ99704 (Uniprot-TrEMBL)
p-Y-IRS1 [cytosol]ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS2 [cytosol]ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y-IRS2 [plasma membrane]ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y-IRS4 [plasma membrane]ProteinO14654 (Uniprot-TrEMBL)
p-Y-SHC1 [cytosol]ProteinP29353 (Uniprot-TrEMBL)
p-Y-SHC2 [cytosol]ProteinP98077 (Uniprot-TrEMBL)
p-Y-SHC3 [cytosol]ProteinQ92529 (Uniprot-TrEMBL)
p-Y1161,Y1165,Y1166-IGF1R(741-1367) [plasma membrane]ProteinP08069 (Uniprot-TrEMBL)
p-Y194,Y195,Y272-SHC1-1(156-583) [plasma membrane]ProteinP29353-3 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2 [plasma membrane]ProteinP29353-2 (Uniprot-TrEMBL)
p-Y349,Y350,Y427-SHC1 [plasma membrane]ProteinP29353-1 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 [cytosol]ProteinQ06124 (Uniprot-TrEMBL)
p21 RAS:GDPComplexREACT_2657 (Reactome)
p21 RAS:GTPComplexREACT_4782 (Reactome)
phospho-IRS:PI3KComplexREACT_3175 (Reactome)
phospho-IRSProteinREACT_4422 (Reactome)
phosphorylated

FGFR1c [plasma

membrane]		ProteinP11362-1 (Uniprot-TrEMBL)
phosphorylated

FGFR3b [plasma

membrane]		ProteinP22607-2 (Uniprot-TrEMBL)
phosphorylated

FGFR3c [plasma

membrane]		ProteinP22607-1 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
3',5'-Cyclic AMPREACT_325 (Reactome)
ADPArrowREACT_150135 (Reactome)
ADPArrowREACT_150227 (Reactome)
ADPArrowREACT_150288 (Reactome)
ADPArrowREACT_1878 (Reactome)
ADPArrowREACT_244 (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_325 (Reactome)
ATPREACT_150135 (Reactome)
ATPREACT_150227 (Reactome)
ATPREACT_150288 (Reactome)
ATPREACT_1878 (Reactome)
ATPREACT_244 (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)
Activated PI3Kmim-catalysisREACT_244 (Reactome)
Activated mTORC1ArrowREACT_6851 (Reactome)
Activated mTORC1mim-catalysisREACT_6873 (Reactome)
Activated mTORC1mim-catalysisREACT_6948 (Reactome)
EEF2KREACT_6883 (Reactome)
EIF4B(2-118)REACT_6778 (Reactome)
EIF4EArrowREACT_6742 (Reactome)
EIF4G1REACT_6870 (Reactome)
GDPArrowREACT_1672 (Reactome)
GDPArrowREACT_2010 (Reactome)
GDPArrowREACT_6895 (Reactome)
GRB2:SOS1REACT_176 (Reactome)
GRB2:SOS1REACT_646 (Reactome)
GRB2:SOS:IRS-PArrowREACT_646 (Reactome)
GRB2:SOS:IRS-Pmim-catalysisREACT_1672 (Reactome)
GRB2:SOS:Phospho-SHCArrowREACT_176 (Reactome)
GRB2:SOS:Phospho-SHCmim-catalysisREACT_2010 (Reactome)
GTPREACT_1672 (Reactome)
GTPREACT_2010 (Reactome)
GTPREACT_6895 (Reactome)
H2OREACT_325 (Reactome)
IGF1/2:IGF1RArrowREACT_150464 (Reactome)
IGF1/2:IGF1RREACT_150288 (Reactome)
IGF1/2:IGF1Rmim-catalysisREACT_150288 (Reactome)
IGF1/2:p-IGF1R:IRS1/2/4REACT_150135 (Reactome)
IGF1/2:p-IGF1R:IRS1/2/4mim-catalysisREACT_150135 (Reactome)
IGF1/2:p-IGF1R:IRS1/4ArrowREACT_150315 (Reactome)
IGF1/2:p-IGF1R:IRS2ArrowREACT_150340 (Reactome)
IGF1/2:p-IGF1R:SHC1ArrowREACT_150430 (Reactome)
IGF1/2:p-IGF1R:SHC1REACT_150227 (Reactome)
IGF1/2:p-IGF1R:SHC1mim-catalysisREACT_150227 (Reactome)
IGF1/2:p-IGF1R:p-IRS1/2/4ArrowREACT_150135 (Reactome)
IGF1/2:p-IGF1R:p-SHC1ArrowREACT_150227 (Reactome)
IGF1/2:p-IGF1RArrowREACT_150288 (Reactome)
IGF1/2:p-IGF1RREACT_150315 (Reactome)
IGF1/2:p-IGF1RREACT_150340 (Reactome)
IGF1/2:p-IGF1RREACT_150430 (Reactome)
IGF1/2REACT_150464 (Reactome)
IGF1RREACT_150464 (Reactome)
IRS1/4REACT_150315 (Reactome)
IRS2REACT_150340 (Reactome)
MLST8REACT_6851 (Reactome)
MTORREACT_6851 (Reactome)
PDE3BREACT_1878 (Reactome)
PDPK1REACT_260 (Reactome)
PI(4,5)P2REACT_244 (Reactome)
PI3KREACT_537 (Reactome)
PIP3:AKT2 complexArrowREACT_1622 (Reactome)
PIP3:AKT2 complexREACT_908 (Reactome)
PIP3:PDK1 complexArrowREACT_260 (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)
PKB regulatorArrowREACT_1622 (Reactome)
PKB:PKB RegulatorREACT_1622 (Reactome)
REACT_150135 (Reactome) Phosphorylated IGF1R phosphorylates IRS1 (Siemeister et al. 1995, Xu et al. 1995, Takahashi et al. 1997, Rakatzi et al. 2006), IRS2 (Kim et al. 1998, Kim et al. 2004), and IRS4 (Fantin et al.1998, Karas et al. 2001, Cuevas et al. 2007) on numerous tyrosine residues. IRS4 is phosphorylated by IGF1R in HEK cells but not in primary muscle cells (Fantin et al. 1998, Schreyer et al. 2003). The phosphotyrosine resideus create binding sites for downstream effectors such as GRB2:SOS and PI3K.
REACT_150227 (Reactome) The phosphorylated IGF1R phosphorylates SHC1 (Giorgetti et al. 1994, Hernandez-Sanchez et al. 1995, Kim et al. 1998). Phosphorylation of SHC1 is sustained whereas phosphorylation of IRS2 by IGF1R is transient (Kim et al. 1998).
REACT_150288 (Reactome) The beta peptide of the type 1 insulin-like growth factor (IGF1R) spans the plasma membrane and trans-autophosphorylates tyrosine residues in response to binding of either IGF1 or IGF2 by the extracellular alpha peptide (LeBon et al. 1986, Yu et al. 1986, Doronio et al. 1990, Hernandez-Sanchez et al. 1995, Alvino et al. 2001).
REACT_150315 (Reactome) IRS1 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (Craparo et al. 1995, He et al. 1995, Huang et al. 2001). IRS4 is also involved in signaling by IGF1R and is presumed to bind phosphorylated IGF1R in the same way as IRS1 (Qu et al. 1999, Cuevas et al. 2007). IRS1 and IRS4 are located at the plasma membrane (Karlsson et al. 2004, Fantin et al. 1998).
REACT_150340 (Reactome) IRS2 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (He et al. 1996, Kim et al. 1998). IRS2 is cytosolic while IRS1 and IRS4 are located in the plasma membrane.
REACT_150430 (Reactome) SHC1 binds the NPEY-juxtamembrane motif of the phosphorylated insulin-like growth factor receptor (IGF1R) (Giorgetti et al. 1994, Tartare-Deckert et al. 1995).
REACT_150464 (Reactome) Either IGF1 (IGF-I) or IGF2 (IGF-II) can bind the type 1 insulin-like growth factor receptor (IGF1R) (Casella et al. 1986, LeBon et al. 1986, Maly and Luthi 1986, Cacieri et al. 1988, Steele-Perkins et al. 1988, Burgisser et al. 1991, Germain-Lee et al. 1992, Keyhanfar et al. 2007, Alvino et al. 2009, Alvino et al. 2011). IGF1R has similar affinities for IGF1 and IGF2 (Casella et al. 1986, Steele-Perkins et al. 1988). The binding sites for IGF1 and IGF2 are in a similar location on the alpha peptide of IGF1R but there are some differences in which residues of IGF1R interact with IGF1 vs. IGF2 (Keyhanfar et al. 2007, Alvino et al. 2009, Alvino et al. 2011).
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_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_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_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_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_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_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_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_6851 (Reactome)
Rheb:GDPREACT_6895 (Reactome)
Rheb:GTPArrowREACT_6895 (Reactome)
Rheb:GTPREACT_6851 (Reactome)
SHC1REACT_150430 (Reactome)
TSC1:Inhibited TSC2-1-PArrowREACT_6952 (Reactome)
TSC1:TSC2REACT_6952 (Reactome)
TSC2REACT_6725 (Reactome)
eIF4E:4E-BP1-PArrowREACT_6873 (Reactome)
eIF4E:4E-BP1-PREACT_6742 (Reactome)
eIF4E:4E-BPREACT_6873 (Reactome)
p-5S-RPS6ArrowREACT_6912 (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-1TBarREACT_6948 (Reactome)
p-S939,S1130,T1462-TSC2ArrowREACT_6725 (Reactome)
p-SHCREACT_176 (Reactome)
p-T37,T46-EIF4EBP1ArrowREACT_6742 (Reactome)
p21 RAS:GDPREACT_1672 (Reactome)
p21 RAS:GDPREACT_2010 (Reactome)
p21 RAS:GTPArrowREACT_1672 (Reactome)
p21 RAS:GTPArrowREACT_2010 (Reactome)
phospho-IRS:PI3KArrowREACT_537 (Reactome)
phospho-IRSREACT_537 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP2677"
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