Signaling by Insulin receptor (Homo sapiens)

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579, 22, 36417, 3531, 44407, 5126, 41469, 22, 36414, 27, 5754415, 172, 331, 7, 101123327, 1050, 589, 22, 3654, 5512, 21, 24, 29, 37...202, 39, 56cytosolendosome lumenATP6V1E2 ATP6V0D2 2xHC-INS(25-54) p-Y427-SHC1 ATP6V0A1 GRB10 ATP6V0B ATP6V0E1 ATP6V0A2 HRAS 4xHC-INS(90-110) GRB2-1:SOS1:p-Y427-SHC1INSR(28-758) ATP6V1G2 ATP6V0D1 p-Y-IRS1 p-Y-IRS:Insulin:p-6Y-Insulin receptorINSR(28-758) GRB2-1 ATP6V1B2 PiPIK3CB ATP6V0E2 MAPK3,(MAPK1)IDAinsulinATP6V0E2 GTP IRS1,IRS2p-Y-IRS1 GRB2-1 ATP6V1C1 ATPATP6V0C p-Y-IRS1 GRB2-1 IRS1 SOS1 INSR(28-758) ATP6V1F ATP6V1G1 Pip-Y-IRS1,p-Y-IRS2ATP6V1A ATP6V0A2 Insulin receptorV-ATPase:ATP6AP1GRB2-1:p-4S-SOS1ATP6V1B2 p-6Y-INSR(763-1382) INSR(763-1382) V-ATPasep-Y427-SHC1ATP6V1E2 INSR(763-1382) GRB2-1:p-4S-SOS1:p-Y427-SHC1INSR(28-758) 4xHC-INS(90-110) 2xHC-INS(25-54) p-6Y-INSR(763-1382) H+2xHC-INS(25-54) ATP6V0D1 ATP6V0E1 ATP6V1D INS(90-110) protein tyrosinephosphataseINSR(28-758) ATP6V1G3 ATP6V1A ATP6V1F 4xHC-INS(90-110) p-Y-IRS1,p-Y-IRS2:PI3KATP6V1E1 INSR(28-758) GTPGDP 4xHC-INS(90-110) 4xHC-INS(90-110) p-Y-IRS2 ADP2xHC-INS(25-54) p-4S-SOS1 ATPInsulin:p-6Y-Insulinreceptor:p-Y427-SHC1SHC1MAPK1 4xHC-INS(90-110) INSR(28-758) ATP6V0C 2xHC-INS(25-54) NRAS KRAS p-4S-SOS1 p-6Y-INSR(763-1382) p-Y-IRS2 PI3KATP6V1C2 PIK3R2 ATP6V1B1 SOS1 IRS:Insulin:p-6Y-Insulin receptorp21 RAS:GTPATP6V1H GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2GRB2-1 4xHC-INS(90-110) 2xHC-INS(25-54) INSR(28-758) ATPp21 RAS:GDPATP6V1C2 2xHC-INS(25-54) p-Y-IRS1 p-6Y-INSR(763-1382) INS(25-54) GRB2-1:SOS1Insulin:p-6Y-Insulinreceptor2xHC-INS(25-54) PIK3CB ATP6V1G2 GRB10:INSRTCIRG1 p-6Y-insulinreceptorGDPPIK3R2 TCIRG1 ATP6V0D2 ATPH+ADPInsulin:InsulinreceptorGRB2-1 HRAS ADPINS(25-54) p-6Y-INSR(763-1382) ATP6V1H Insulin:p-6Y-Insulinreceptor:SHC1PIK3R1 ATP6V1C1 IRS2 INSR(28-758) INSR(763-1382) ATP6V1B1 mTOR signallingGRB2:p-4S-SOS1:p-Y-IRS1,p-Y-IRS2p-Y-IRS1 GRB2-1 ATPp-Y427-SHC1 SOS1p-Y-IRS2 PIK3CA p-Y427-SHC1 RAF/MAP kinasecascadeADPPIK3R1 InsulinATP6V1D NRAS ATP6V1E1 INS(90-110) p-6Y-INSR(763-1382) GRB2-1ATP6V0A4 PIK3CA ATP6V1G1 p-Y-IRS2 p-Y-IRS2 SOS1 ATP6V0B Insulin:p-6Y-insulinreceptorATP6AP1 ATP6V0A1 PiIRS2 PI3K CascadeADPSHC1 p-6Y-INSR(763-1382) p-4S-SOS1 ATP6V1G3 KRAS protein tyrosinephosphataseINSR(28-758) insulin receptorATP6AP14xHC-INS(90-110) p-6Y-INSR(763-1382) MAPK3 GRB10IRS1 ATP6V0A4 INSR(28-758) 483, 6, 8, 16, 18...13, 1430, 4715, 373815, 37


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 (Slc2a4) 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. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 74752
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Bevan, A Paul

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Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
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

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NameTypeDatabase referenceComment
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATP6AP1 ProteinQ15904 (Uniprot-TrEMBL)
ATP6AP1ProteinQ15904 (Uniprot-TrEMBL)
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)
ATP6V1E1 ProteinP36543 (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)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB10 ProteinQ13322 (Uniprot-TrEMBL)
GRB10:INSRComplexR-HSA-110010 (Reactome)
GRB10ProteinQ13322 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2ComplexR-HSA-109800 (Reactome)
GRB2-1:SOS1:p-Y427-SHC1ComplexR-HSA-109798 (Reactome)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1:p-4S-SOS1:p-Y427-SHC1ComplexR-HSA-5686063 (Reactome)
GRB2-1:p-4S-SOS1ComplexR-HSA-109801 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:p-4S-SOS1:p-Y-IRS1,p-Y-IRS2ComplexR-HSA-5686316 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
IDAR-HSA-74819 (Reactome)
INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
INSR(28-758) ProteinP06213 (Uniprot-TrEMBL)
INSR(763-1382) ProteinP06213 (Uniprot-TrEMBL)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS1,IRS2ComplexR-HSA-74698 (Reactome) The proteins mentioned here are examples of IRS family members acting as indicated for IRS.
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
IRS:Insulin:p-6Y-Insulin receptorComplexR-HSA-74699 (Reactome)
Insulin receptorComplexR-HSA-74675 (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.
Insulin:Insulin receptorComplexR-HSA-74703 (Reactome)
Insulin:p-6Y-Insulin receptor:SHC1ComplexR-HSA-74681 (Reactome)
Insulin:p-6Y-Insulin receptor:p-Y427-SHC1ComplexR-HSA-74685 (Reactome)
Insulin:p-6Y-Insulin receptorComplexR-HSA-74678 (Reactome)
Insulin:p-6Y-insulin receptorComplexR-HSA-74702 (Reactome)
InsulinComplexR-HSA-74674 (Reactome)
KRAS ProteinP01116 (Uniprot-TrEMBL)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPK3,(MAPK1)ComplexR-HSA-3656389 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
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)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
TCIRG1 ProteinQ13488 (Uniprot-TrEMBL)
V-ATPase:ATP6AP1ComplexR-HSA-5252081 (Reactome)
V-ATPaseComplexR-HSA-912600 (Reactome)
insulin receptorComplexR-HSA-74706 (Reactome)
insulinComplexR-HSA-77385 (Reactome)
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-4S-SOS1 ProteinQ07889 (Uniprot-TrEMBL)
p-6Y-INSR(763-1382) ProteinP06213 (Uniprot-TrEMBL)
p-6Y-insulin receptorComplexR-HSA-77384 (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-Y-IRS:Insulin:p-6Y-Insulin receptorComplexR-HSA-74695 (Reactome)
p-Y427-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y427-SHC1ProteinP29353 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
protein tyrosine phosphataseR-HSA-74731 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-109822 (Reactome)
ADPArrowR-HSA-109823 (Reactome)
ADPArrowR-HSA-74711 (Reactome)
ADPArrowR-HSA-74715 (Reactome)
ADPArrowR-HSA-74742 (Reactome)
ATP6AP1R-HSA-5252133 (Reactome)
ATPR-HSA-109822 (Reactome)
ATPR-HSA-109823 (Reactome)
ATPR-HSA-74711 (Reactome)
ATPR-HSA-74715 (Reactome)
ATPR-HSA-74742 (Reactome)
GDPArrowR-HSA-109807 (Reactome)
GDPArrowR-HSA-109817 (Reactome)
GRB10:INSRArrowR-HSA-110011 (Reactome)
GRB10:INSRTBarR-HSA-74707 (Reactome)
GRB10:INSRTBarR-HSA-74740 (Reactome)
GRB10R-HSA-110011 (Reactome)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2ArrowR-HSA-74736 (Reactome)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2R-HSA-109823 (Reactome)
GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2mim-catalysisR-HSA-109817 (Reactome)
GRB2-1:SOS1:p-Y427-SHC1ArrowR-HSA-74746 (Reactome)
GRB2-1:SOS1:p-Y427-SHC1R-HSA-109822 (Reactome)
GRB2-1:SOS1:p-Y427-SHC1mim-catalysisR-HSA-109807 (Reactome)
GRB2-1:SOS1ArrowR-HSA-109813 (Reactome)
GRB2-1:SOS1R-HSA-74736 (Reactome)
GRB2-1:SOS1R-HSA-74746 (Reactome)
GRB2-1:p-4S-SOS1:p-Y427-SHC1ArrowR-HSA-109822 (Reactome)
GRB2-1:p-4S-SOS1:p-Y427-SHC1R-HSA-5686074 (Reactome)
GRB2-1:p-4S-SOS1ArrowR-HSA-5686074 (Reactome)
GRB2-1:p-4S-SOS1ArrowR-HSA-5686315 (Reactome)
GRB2-1R-HSA-109813 (Reactome)
GRB2:p-4S-SOS1:p-Y-IRS1,p-Y-IRS2ArrowR-HSA-109823 (Reactome)
GRB2:p-4S-SOS1:p-Y-IRS1,p-Y-IRS2R-HSA-5686315 (Reactome)
GTPR-HSA-109807 (Reactome)
GTPR-HSA-109817 (Reactome)
H+ArrowR-HSA-74723 (Reactome)
H+R-HSA-74723 (Reactome)
IDAmim-catalysisR-HSA-74730 (Reactome)
IRS1,IRS2ArrowR-HSA-74747 (Reactome)
IRS1,IRS2R-HSA-74707 (Reactome)
IRS:Insulin:p-6Y-Insulin receptorArrowR-HSA-74707 (Reactome)
IRS:Insulin:p-6Y-Insulin receptorR-HSA-74711 (Reactome)
IRS:Insulin:p-6Y-Insulin receptormim-catalysisR-HSA-74711 (Reactome)
Insulin receptorArrowR-HSA-74734 (Reactome)
Insulin receptorR-HSA-74716 (Reactome)
Insulin:Insulin receptorArrowR-HSA-74716 (Reactome)
Insulin:Insulin receptorR-HSA-74715 (Reactome)
Insulin:Insulin receptormim-catalysisR-HSA-74715 (Reactome)
Insulin:p-6Y-Insulin receptor:SHC1ArrowR-HSA-74740 (Reactome)
Insulin:p-6Y-Insulin receptor:SHC1R-HSA-74742 (Reactome)
Insulin:p-6Y-Insulin receptor:SHC1mim-catalysisR-HSA-74742 (Reactome)
Insulin:p-6Y-Insulin receptor:p-Y427-SHC1ArrowR-HSA-74742 (Reactome)
Insulin:p-6Y-Insulin receptor:p-Y427-SHC1R-HSA-74743 (Reactome)
Insulin:p-6Y-Insulin receptorArrowR-HSA-74712 (Reactome)
Insulin:p-6Y-Insulin receptorArrowR-HSA-74715 (Reactome)
Insulin:p-6Y-Insulin receptorArrowR-HSA-74743 (Reactome)
Insulin:p-6Y-Insulin receptorR-HSA-110011 (Reactome)
Insulin:p-6Y-Insulin receptorR-HSA-74707 (Reactome)
Insulin:p-6Y-Insulin receptorR-HSA-74718 (Reactome)
Insulin:p-6Y-Insulin receptorR-HSA-74740 (Reactome)
Insulin:p-6Y-insulin receptorArrowR-HSA-74718 (Reactome)
Insulin:p-6Y-insulin receptorR-HSA-74726 (Reactome)
InsulinR-HSA-74716 (Reactome)
MAPK3,(MAPK1)mim-catalysisR-HSA-109822 (Reactome)
MAPK3,(MAPK1)mim-catalysisR-HSA-109823 (Reactome)
PI3KR-HSA-74737 (Reactome)
PiArrowR-HSA-74733 (Reactome)
PiArrowR-HSA-74747 (Reactome)
PiArrowR-HSA-74748 (Reactome)
R-HSA-109807 (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-109813 (Reactome) In the cytoplasm of unstimulated cells, SOS1 is found in a complex with GRB2. The interaction occurs between the carboxy terminal domain of SOS1 and the Src homology 3 (SH3) domains of GRB2.
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-109822 (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.
R-HSA-109823 (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'.

R-HSA-110011 (Reactome) Grb10 negatively regulates the insulin-dependent phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor (Wick et al, 2003;Langlais et al, 2004).
R-HSA-5252133 (Reactome) Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular cargos and deliver protons across the plasma membrane of many specialised cells. V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0 subcomplex of V-ATPase, facilitating acidification (Supek et al. 1994). Experiments with the mouse orthologue reveals a role for Atp6ap1 in osteoclast formation and function (Qin et al. 2011).
R-HSA-5686074 (Reactome) p-Y427-SHC1 dissociates from GRB2-1:p-4S-SOS1
R-HSA-5686315 (Reactome) p-Y-IRS1,p-Y-IRS2 dissociates from GRB2-1:p-4S-SOS1
R-HSA-74707 (Reactome) Using receptor mutagenesis studies it is known that IRS1 via its PTB domain binds to the insulin receptor at the juxtamembrane region at tyrosine 972. The interaction is further stabilized by the PH domain of IRS1 which interacts with the phospholipids of the plasma membrane. This allows the receptor to phosphorylate IRS1 on up to 13 of its tyrosine residues (Tavare and Denton 1998, Duan et al.2004).
R-HSA-74711 (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'.

R-HSA-74712 (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'. In Fao or NIH3T3 cells stably expressing IR, overexpression of PKCζ enhances the dissociation from IR and decrease in IRS1 tyrosine phosphorylation caused by prolonged insulin stimulation (Riu et al. 2001, Ravichandran et al. 2001).
R-HSA-74715 (Reactome) Receptor autophosphorylation requires a lysine at position 1057 to stabilize the gamma phosphate of ATP. The adenosine of ATP interacts with three glycines at residues 1030-1035. The first tyrosine residues to be autophosphorylated are 1185, 1189 and 1190 in the kinase domain. This is followed by 999 in the juxtamembrane domain, 1355 and 1361. 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, where the beta-subunits phosphorylate each other rather than themselves (Tavaré et al. 1998).
R-HSA-74716 (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. The insulin receptor is a tetramer, consisting of two alpha and two beta chains, which are produced by cleavage of a single translated peptide chain (Schenker & Kohanski 1991). 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.

R-HSA-74718 (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.)

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.

R-HSA-74723 (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).
R-HSA-74726 (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.
R-HSA-74730 (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)'.

R-HSA-74733 (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.)

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

R-HSA-74734 (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.

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).
R-HSA-74740 (Reactome) SHC1 interacts via its SH2 domain with the carboxyterminal phosphorylated tyrosines of the insulin receptor. As a result, SHC1 is tyrosine phosphorylated by the insulin receptor, later falling away from the receptor (Liang et al.1999, Sasaoka et al.1996).
R-HSA-74742 (Reactome) SHC1 is tyrosine phosphorylated at Tyr-427 by the insulin receptor, later falling away from the receptor. Phosphorylation of SHC1 allows the SH2 domain of GRB2 to bind it (Sasaoka et al. 2000).
R-HSA-74743 (Reactome) Release of tyrosine-phosphorylated SHC from the insulin receptor triggers a cascade of signalling events via SOS, RAF and the MAP kinases (Sasaoka et al. 1996, Kleiman et al.2011). This is a black box event since this dissociation is inferred from other reaction which show association and dissociation for this protein under EGF stimulation (Kleiman et al. 2011).
R-HSA-74746 (Reactome) Tyrosine-phosphorylated SHC1 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.
R-HSA-74747 (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' (Pederson et al.2001).

R-HSA-74748 (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' (Sasaoka et al. 1996).
This is a black box event since the event of dephosphorylation is inferred from other reaction where this process occurs after other stimulation (Gu et al. 1999).
SHC1ArrowR-HSA-74748 (Reactome)
SHC1R-HSA-74740 (Reactome)
SOS1R-HSA-109813 (Reactome)
V-ATPase:ATP6AP1ArrowR-HSA-5252133 (Reactome)
V-ATPase:ATP6AP1mim-catalysisR-HSA-74723 (Reactome)
V-ATPaseR-HSA-5252133 (Reactome)
insulin receptorArrowR-HSA-74733 (Reactome)
insulin receptorR-HSA-74734 (Reactome)
insulinArrowR-HSA-74726 (Reactome)
insulinR-HSA-74730 (Reactome)
p-6Y-insulin receptorArrowR-HSA-74726 (Reactome)
p-6Y-insulin receptorR-HSA-74733 (Reactome)
p-Y-IRS1,p-Y-IRS2:PI3KArrowR-HSA-74737 (Reactome)
p-Y-IRS1,p-Y-IRS2ArrowR-HSA-5686315 (Reactome)
p-Y-IRS1,p-Y-IRS2ArrowR-HSA-74712 (Reactome)
p-Y-IRS1,p-Y-IRS2R-HSA-74736 (Reactome)
p-Y-IRS1,p-Y-IRS2R-HSA-74737 (Reactome)
p-Y-IRS1,p-Y-IRS2R-HSA-74747 (Reactome)
p-Y-IRS:Insulin:p-6Y-Insulin receptorArrowR-HSA-74711 (Reactome)
p-Y-IRS:Insulin:p-6Y-Insulin receptorR-HSA-74712 (Reactome)
p-Y427-SHC1ArrowR-HSA-5686074 (Reactome)
p-Y427-SHC1ArrowR-HSA-74743 (Reactome)
p-Y427-SHC1R-HSA-74746 (Reactome)
p-Y427-SHC1R-HSA-74748 (Reactome)
p21 RAS:GDPR-HSA-109807 (Reactome)
p21 RAS:GDPR-HSA-109817 (Reactome)
p21 RAS:GTPArrowR-HSA-109807 (Reactome)
p21 RAS:GTPArrowR-HSA-109817 (Reactome)
protein tyrosine phosphatasemim-catalysisR-HSA-74733 (Reactome)
protein tyrosine phosphatasemim-catalysisR-HSA-74747 (Reactome)
protein tyrosine phosphatasemim-catalysisR-HSA-74748 (Reactome)

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