Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) (Homo sapiens)

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1, 19, 33, 34, 36...2, 15, 17, 20, 356, 9, 27, 29, 39...8, 15, 393, 82, 23, 26, 30, 35...39, 548, 15, 394, 16, 22, 32, 49...415838cytosolp21 RAS:GDPIGF1 PIK3R2 IGF2(25-91) IGF1R(31-736) NRAS SHC1 ATPIGF2(25-91) GRB2-1:SOS1p-Y349,Y350,Y427-SHC1-1 HRAS SHC1-1(156-583) IGF1R(741-1367) SHC1p-Y-IRS1 PIK3R1 IGF2(25-91) GRB2-1 IRS4 p-Y194,Y195,Y272-SHC1-3 RAF/MAP kinasecascadeIGF1,2:p-3Y-IGF1R:p-3Y-SHC1IGF2(25-91) p-Y1161,Y1165,Y1166-IGF1R(741-1367) IGF1 IGF1,2:p-IGF1R:IRS1,4p-Y-IRS2 IRS1 PIK3CB p-Y-IRS1,p-Y-IRS2IRS4 p21 RAS:GTPHRAS p-Y349,Y350,Y427-SHC1-1 IGF2(25-91) mTOR signallingGDP ADPp-Y1161,Y1165,Y1166-IGF1R(741-1367) PIK3R2 SOS1 IGF1R(31-736) PIK3R1 PIK3CA IGF1RSOS1 IRS1 IGF1,2:p-IGF1R:IRS2GRB2-1:SOS1:p-3Y-SHC1GRB2-1 IGF1R(31-736) IRS2PIK3CB IGF1R(31-736) GDPIGF1,2:p-Y1161,1165,1166-IGF1R:SHC1IGF1 p-Y194,Y195,Y272-SHC1-3 GTPp-Y1161,Y1165,Y1166-IGF1R(741-1367) SHC1-2 p-Y1161,Y1165,Y1166-IGF1R(741-1367) IGF1,2:p-Y1161,1165,1166-IGF1Rp-Y-IRS1 SHC1 KRAS IGF1R(31-736) ADPGTP p-Y239,Y240,Y317-SHC1-2 NRAS p-Y239,Y240,Y317-SHC1-2 IGF1,2IGF1R(31-736) SHC1-2 IGF1 PI3K CascadeIRS2 p-Y-IRS2 p-Y-IRS2 PI3Kp-Y-IRS1 GRB2-1 IGF1R(741-1367) KRAS IGF2(25-91) IGF1R(31-736) IGF1 glc-fuc-CILPATPIRS1,4IGF1,2:IGF1Rp-Y194,Y195,Y272-SHC1-3 PIK3CA SHC1-1(156-583) IGF1 IGF2(25-91) p-3Y-SHC1p-Y-IRS1,p-Y-IRS2:PI3KGRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2SOS1 p-Y1161,Y1165,Y1166-IGF1R(741-1367) p-Y239,Y240,Y317-SHC1-2 IGF1 p-Y349,Y350,Y427-SHC1-1 55245, 7, 10, 12-14, 18...2111245525, 5639, 55


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). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 2404192
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
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

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1:p-3Y-SHC1ComplexR-HSA-5686070 (Reactome)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2ComplexR-HSA-109800 (Reactome)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
IGF1 ProteinP05019 (Uniprot-TrEMBL)
IGF1,2:IGF1RComplexR-HSA-2404186 (Reactome)
IGF1,2:p-3Y-IGF1R:p-3Y-SHC1ComplexR-HSA-2404190 (Reactome)
IGF1,2:p-IGF1R:IRS1,4ComplexR-HSA-2428923 (Reactome)
IGF1,2:p-IGF1R:IRS2ComplexR-HSA-2428931 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1R:SHC1ComplexR-HSA-2404185 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1RComplexR-HSA-2404189 (Reactome)
IGF1,2ComplexR-HSA-381451 (Reactome)
IGF1R(31-736) ProteinP08069 (Uniprot-TrEMBL)
IGF1R(741-1367) ProteinP08069 (Uniprot-TrEMBL)
IGF1RComplexR-HSA-2404182 (Reactome)
IGF2(25-91) ProteinP01344 (Uniprot-TrEMBL)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS1,4ComplexR-HSA-2428932 (Reactome)
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
IRS2ProteinQ9Y4H2 (Uniprot-TrEMBL)
IRS4 ProteinO14654 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PI3K CascadePathwayR-HSA-109704 (Reactome) The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival.
PI3KComplexR-HSA-74693 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
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).
SHC1 ProteinP29353-1 (Uniprot-TrEMBL)
SHC1-1(156-583) ProteinP29353-3 (Uniprot-TrEMBL)
SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
SHC1ComplexR-HSA-2404191 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
glc-fuc-CILPProteinO75339 (Uniprot-TrEMBL)
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.
p-3Y-SHC1ComplexR-HSA-2404184 (Reactome)
p-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS1,p-Y-IRS2:PI3KComplexR-HSA-74694 (Reactome)
p-Y-IRS1,p-Y-IRS2ComplexR-HSA-112322 (Reactome)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y1161,Y1165,Y1166-IGF1R(741-1367) ProteinP08069 (Uniprot-TrEMBL)
p-Y194,Y195,Y272-SHC1-3 ProteinP29353-3 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
p-Y349,Y350,Y427-SHC1-1 ProteinP29353-1 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-2404193 (Reactome)
ADPArrowR-HSA-2404199 (Reactome)
ATPR-HSA-2404193 (Reactome)
ATPR-HSA-2404199 (Reactome)
GDPArrowR-HSA-109817 (Reactome)
GDPArrowR-HSA-5686318 (Reactome)
GRB2-1:SOS1:p-3Y-SHC1ArrowR-HSA-5686073 (Reactome)
GRB2-1:SOS1:p-3Y-SHC1mim-catalysisR-HSA-5686318 (Reactome)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2ArrowR-HSA-74736 (Reactome)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2mim-catalysisR-HSA-109817 (Reactome)
GRB2-1:SOS1R-HSA-5686073 (Reactome)
GRB2-1:SOS1R-HSA-74736 (Reactome)
GTPR-HSA-109817 (Reactome)
GTPR-HSA-5686318 (Reactome)
IGF1,2:IGF1RArrowR-HSA-2404200 (Reactome)
IGF1,2:IGF1RR-HSA-2404199 (Reactome)
IGF1,2:IGF1Rmim-catalysisR-HSA-2404199 (Reactome)
IGF1,2:p-3Y-IGF1R:p-3Y-SHC1ArrowR-HSA-2404193 (Reactome)
IGF1,2:p-3Y-IGF1R:p-3Y-SHC1R-HSA-5686072 (Reactome)
IGF1,2:p-IGF1R:IRS1,4ArrowR-HSA-2428930 (Reactome)
IGF1,2:p-IGF1R:IRS2ArrowR-HSA-2428922 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1R:SHC1ArrowR-HSA-2404195 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1R:SHC1R-HSA-2404193 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1R:SHC1mim-catalysisR-HSA-2404193 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1RArrowR-HSA-2404199 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1RArrowR-HSA-5686072 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1RR-HSA-2404195 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1RR-HSA-2428922 (Reactome)
IGF1,2:p-Y1161,1165,1166-IGF1RR-HSA-2428930 (Reactome)
IGF1,2R-HSA-2404200 (Reactome)
IGF1RR-HSA-2404200 (Reactome)
IRS1,4R-HSA-2428930 (Reactome)
IRS2R-HSA-2428922 (Reactome)
PI3KR-HSA-74737 (Reactome)
R-HSA-109817 (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.
R-HSA-2404193 (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).
R-HSA-2404195 (Reactome) SHC binds the NPEY-juxtamembrane motif of the phosphorylated insulin-like growth factor receptor (IGF1R) (Giorgetti et al. 1994, Tartare-Deckert et al. 1995).
R-HSA-2404199 (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).
R-HSA-2404200 (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).
R-HSA-2428922 (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.
R-HSA-2428930 (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).
R-HSA-5686072 (Reactome) Release of tyrosine-phosphorylated SHC from IGF1R triggers a cascade of signalling events via SOS, RAF and the MAP kinases.
R-HSA-5686073 (Reactome) Phosphorylated SHC1 recruits the SH2 domain of the adaptor protein GRB2, which is in a complex with SOS, an exchange factor for p21ras and RAC. 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.
R-HSA-5686318 (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.
R-HSA-74736 (Reactome) Inactive p21ras:GDP is anchored to the plasma membrane by a farnesyl residue. Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues. GRB2 binds the phosphotyrosines via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the GRB2:SOS1:IRS interaction brings SOS1 and p21 Ras into close proximity.
R-HSA-74737 (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 (Rivachandran et al. 2001).
SHC1R-HSA-2404195 (Reactome)
glc-fuc-CILPTBarR-HSA-2404199 (Reactome)
p-3Y-SHC1ArrowR-HSA-5686072 (Reactome)
p-3Y-SHC1R-HSA-5686073 (Reactome)
p-Y-IRS1,p-Y-IRS2:PI3KArrowR-HSA-74737 (Reactome)
p-Y-IRS1,p-Y-IRS2R-HSA-74736 (Reactome)
p-Y-IRS1,p-Y-IRS2R-HSA-74737 (Reactome)
p21 RAS:GDPR-HSA-109817 (Reactome)
p21 RAS:GDPR-HSA-5686318 (Reactome)
p21 RAS:GTPArrowR-HSA-109817 (Reactome)
p21 RAS:GTPArrowR-HSA-5686318 (Reactome)
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