Signaling by insulin receptor (Homo sapiens)

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15-174-682998, 3515-1712-142810333130312831, 32101036, 3728195, 715-1726, 272834, 3512, 188, 1120, 2122-2510343131cytosolendosome lumennucleoplasmADPADPADPADPATPinsulin:insulin receptorATPATPATPADPeIF4EIRS:activated insulin receptorATPADPGRB2:phospho-SHCphospho-IRS:activated insulin receptorp21 RAS:GDPphospho-IRSeIF4G-PActivated ERK2ATPATPATPActivated ERK1ATPGTPActivated RAF1 complex:MEK2ADPmLst8Crk:IRS-PADPATPActivated RAF1 complex:MEKinsulinCrk:SOS:IRS-PMEKphospho-ERK-1 dimerGRB2:SOS:IRS-PATPGRB2:IRS-PADPActivated RAF1 complex:MEK1MEK1:ERK-1PKB regulatorADPeIF4E:4E-BP1-Pphospho-SOSGRB2:SOS:Phospho-SHCActivated RAF1 complexATPATPactivated insulin receptorp-(Ser-93, 1130, Thr-1462)-TSC2-1Phosphorylated RaptorH+ATPADPeIF4GPDK1ADPRAF activationS6K1-PRheb:GTPphospho-ERK-1 dimermTORAMPADPGDPGTPMEK2:ERK-2phospho-MEK1eEF2K-Pphospho-insulin receptorphospho-ERK-2:MEK2PIP3:AKT2 complexprotein tyrosine phosphatasePhosphatidylinositol-3,4,5-trisphosphateOrthophosphateSHC1H+ERK240S small ribosomal protein 6ATPphospho-ERK-2 dimerActivated mTORC1Phospho-SHCphospho-MEK2phospho-IRS-1/2p(Y317)-SHCActivated PI3KOrthophosphateactivated insulin receptorTSC2-1H2OIDAATPPIP3:Phosphorylated PKB complex4E-BP1-Pphospho-IRS:PI3Kphospho-SHC: activated insulin receptor3',5'-Cyclic AMPRheb:GDPATPTSC1:Inhibited TSC2-1-PGRB10ADPPIP3:PDK1 complexGRB2:SOS1GDPADPV-ATPaseADPTSC1:TSC2Phosphorylated 40S small ribosomal protein 6ERK1eIF4BGRB10:INSReIF4E:4E-BPphospho-ERK-2 dimerRaptorSHC:activated insulin receptorADPinsulin receptorphospho_MEK1ADPMEK1PI3KInsulin receptorADPPhosphorylated PDE3BinsulinIRSPhosphatidyl-myo-inositol 4,5-bisphosphateeEF2Kphospho-Cdc2 (Thr 161)phospho-ERK-1:MEK1Phosphodiesterase 3BPKB:PKB RegulatorATPS6K1eIF4B-Pp21 RAS:GTP1, 23


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.</div>

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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
3',5'-Cyclic AMP Metabolite17489 (ChEBI)
40S small ribosomal

protein 6

ProteinP62753 (UniProt)
4E-BP1-P ProteinQ13541 (UniProt)
ADP Metabolite16761 (ChEBI)
AMP Metabolite16027 (ChEBI)
ATP Metabolite15422 (ChEBI)
Activated ERK1 ProteinP27361 (UniProt)
Activated ERK2 ProteinP28482 (UniProt)
Activated PI3K UnknownREACT_9165 (Reactome)
Activated RAF1

complex

ComplexREACT_4906 (Reactome)
Activated RAF1

complex:MEK

ComplexREACT_3953 (Reactome)
Activated RAF1

complex:MEK1

ComplexREACT_4256 (Reactome)
Activated RAF1

complex:MEK2

ComplexREACT_4223 (Reactome)
Activated mTORC1 ComplexREACT_7770 (Reactome)
Crk:IRS-P ComplexREACT_4822 (Reactome)
Crk:SOS:IRS-P ComplexREACT_2957 (Reactome)
ERK1 ProteinP27361 (UniProt)
ERK2 ProteinP28482 (UniProt)
GDP Metabolite17552 (ChEBI)
GRB10 ProteinQ13322 (UniProt)
GRB10:INSR ComplexREACT_5054 (Reactome)
GRB2:IRS-P ComplexREACT_5160 (Reactome)
GRB2:SOS1 ComplexREACT_4435 (Reactome)
GRB2:SOS:IRS-P ComplexREACT_3414 (Reactome)
GRB2:SOS:Phospho-

SHC

ComplexREACT_2380 (Reactome)
GRB2:phospho-SHC ComplexREACT_2584 (Reactome)
GTP Metabolite15996 (ChEBI)
H+ Metabolite15378 (ChEBI)
H2O Metabolite15377 (ChEBI)
IDA UnknownREACT_2385 (Reactome)
IRS ProteinREACT_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.
IRS:activated insulin

receptor

ComplexREACT_3393 (Reactome)
Insulin receptor ComplexREACT_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.
MEK ProteinREACT_2275 (Reactome)
MEK1 ProteinREACT_2607 (Reactome)
MEK1:ERK-1 ComplexREACT_5539 (Reactome)
MEK2:ERK-2 ComplexREACT_5435 (Reactome)
Orthophosphate Metabolite18367 (ChEBI)
PDK1 ProteinO15530 (UniProt)
PI3K ComplexREACT_4240 (Reactome)
PIP3:AKT2 complex ComplexREACT_4871 (Reactome)
PIP3:PDK1 complex ComplexREACT_5409 (Reactome)
PIP3:Phosphorylated

PKB complex

ComplexREACT_3373 (Reactome)
PKB regulator ProteinREACT_5778 (Reactome)
PKB:PKB Regulator ComplexREACT_4747 (Reactome)
Phosphatidyl-

myo-inositol 4,5- bisphosphate

Unknown18348 (ChEBI)
Phosphatidylinositol-

3,4,5-trisphosphate

Unknown16618 (ChEBI)
Phospho-SHC ProteinREACT_12146 (Reactome)
Phosphodiesterase

3B

ProteinQ13370 (UniProt) Can hydrolyze both cAMP and cGMP
Phosphorylated

PDE3B

ProteinQ13370 (UniProt)
Phosphorylated

Raptor

ProteinQ8N122-1 (UniProt)
Phosphorylated 40S

small ribosomal protein 6

ProteinP62753 (UniProt)
RAF activation PathwayREACT_2077 (Reactome) Phosphorylated RAF is activated by Ras binding and stabilised in its active form by transient disassociation and reassociation of 14-3-3, as well as further phosphorylation.
Raptor ProteinREACT_7195 (Reactome)
Rheb:GDP ComplexREACT_7464 (Reactome)
Rheb:GTP ComplexREACT_7765 (Reactome)
S6K1 ProteinP23443 (UniProt)
S6K1-P ProteinP23443 (UniProt)
SHC1 ProteinP29353 (UniProt)
SHC:activated insulin

receptor

ComplexREACT_3791 (Reactome)
TSC1:Inhibited TSC2-

1-P

ComplexREACT_7650 (Reactome)
TSC1:TSC2 ComplexREACT_7850 (Reactome)
TSC2-1 ProteinP49815-1 (UniProt)
V-ATPase ComplexREACT_24332 (Reactome)
activated insulin

receptor

ComplexREACT_3057 (Reactome)
activated insulin

receptor

ComplexREACT_4836 (Reactome)
eEF2K ProteinO00418 (UniProt)
eEF2K-P ProteinO00418 (UniProt)
eIF4B ProteinP23588 (UniProt)
eIF4B-P ProteinP23588 (UniProt)
eIF4E ProteinP06730 (UniProt)
eIF4E:4E-BP ComplexREACT_3978 (Reactome)
eIF4E:4E-BP1-P ComplexREACT_7838 (Reactome)
eIF4G ProteinQ04637 (UniProt)
eIF4G-P ProteinQ04637 (UniProt)
insulin ComplexREACT_3655 (Reactome)
insulin ComplexREACT_5828 (Reactome)
insulin receptor ComplexREACT_3854 (Reactome)
insulin:insulin

receptor

ComplexREACT_3518 (Reactome)
mLst8 ProteinQ9BVC4 (UniProt)
mTOR ProteinP42345 (UniProt)
p(Y317)-SHC ProteinP29353 (UniProt)
p-(Ser-93, 1130,

Thr-1462)-TSC2-1

ProteinP49815-1 (UniProt)
p21 RAS:GDP ComplexREACT_2657 (Reactome)
p21 RAS:GTP ComplexREACT_4782 (Reactome)
phospho-Cdc2 (Thr

161)

ProteinP06493 (UniProt)
phospho-ERK-1

dimer

ComplexREACT_3152 (Reactome)
phospho-ERK-1

dimer

ComplexREACT_3932 (Reactome)
phospho-ERK-1:

MEK1

ComplexREACT_2796 (Reactome)
phospho-ERK-2

dimer

ComplexREACT_3688 (Reactome)
phospho-ERK-2

dimer

ComplexREACT_5046 (Reactome)
phospho-ERK-2:

MEK2

ComplexREACT_3199 (Reactome)
phospho-IRS ProteinREACT_4422 (Reactome)
phospho-IRS-

1/2

ProteinREACT_4523 (Reactome)
phospho-IRS:

activated insulin receptor

ComplexREACT_4013 (Reactome)
phospho-IRS:PI3K ComplexREACT_3175 (Reactome)
phospho-MEK1 ProteinQ02750 (UniProt)
phospho-MEK2 ProteinP36507 (UniProt)
phospho-SHC:

activated insulin receptor

ComplexREACT_4738 (Reactome)
phospho-SOS ProteinQ07889 (UniProt)
phospho-insulin

receptor

ComplexREACT_3809 (Reactome)
phospho_MEK1 ProteinREACT_3339 (Reactome)
protein tyrosine

phosphatase

UnknownREACT_3980 (Reactome)

Annotated Interactions

No annotated interactions

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