Signaling by Insulin receptor (Homo sapiens)

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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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History

CompareRevisionActionTimeUserComment
45215view17:26, 7 October 2011KhanspersOntology Term : 'insulin signaling pathway' added !
42129view21:59, 4 March 2011MaintBotAutomatic update
39939view05:57, 21 January 2011MaintBotNew pathway

External references

View all 103...

Name Type Database reference
mLst8 ProteinQ9BVC4 (UniProt)
insulin ComplexREACT_5828 (Reactome)
GRB2:phospho-SHC ComplexREACT_2584 (Reactome)
insulin:insulin

receptor

ComplexREACT_3518 (Reactome)
eIF4G ProteinQ04637 (UniProt)
ATP Metabolite15422 (ChEBI)
PIP3:AKT2 complex ComplexREACT_4871 (Reactome)
ADP Metabolite16761 (ChEBI)
eEF2K ProteinO00418 (UniProt)
activated insulin

receptor

ComplexREACT_3057 (Reactome)
Phospho-SHC ProteinREACT_12146 (Reactome)
SHC1 ProteinP29353 (UniProt)
Insulin receptor ComplexREACT_5691 (Reactome)
SHC:activated insulin

receptor

ComplexREACT_3791 (Reactome)
TSC1:Inhibited TSC2-

1-P

ComplexREACT_7650 (Reactome)
phospho-SHC:

activated insulin receptor

ComplexREACT_4738 (Reactome)
S6K1-P ProteinP23443 (UniProt)
p(Y317)-SHC ProteinP29353 (UniProt)
phospho-ERK-2:

MEK2

ComplexREACT_3199 (Reactome)
GRB2:SOS1 ComplexREACT_4435 (Reactome)
eIF4E:4E-BP ComplexREACT_3978 (Reactome)
GRB2:SOS:Phospho-

SHC

ComplexREACT_2380 (Reactome)
MEK1 ProteinREACT_2607 (Reactome)
GTP Metabolite15996 (ChEBI)
GRB10 ProteinQ13322 (UniProt)
p21 RAS:GDP ComplexREACT_2657 (Reactome)
PKB:PKB Regulator ComplexREACT_4747 (Reactome)
GDP Metabolite17552 (ChEBI)
p-(Ser-93, 1130,

Thr-1462)-TSC2-1

ProteinP49815-1 (UniProt)
p21 RAS:GTP ComplexREACT_4782 (Reactome)
Rheb:GTP ComplexREACT_7765 (Reactome)
Activated RAF1

complex

ComplexREACT_4906 (Reactome)
Activated mTORC1 ComplexREACT_7770 (Reactome)
MEK ProteinREACT_2275 (Reactome)
40S small ribosomal

protein 6

ProteinP62753 (UniProt)
Activated RAF1

complex:MEK

ComplexREACT_3953 (Reactome)
ERK2 ProteinP28482 (UniProt)
phospho-MEK1 ProteinQ02750 (UniProt)
phospho-ERK-2

dimer

ComplexREACT_3688 (Reactome)
phospho-MEK2 ProteinP36507 (UniProt)
eIF4B ProteinP23588 (UniProt)
ERK1 ProteinP27361 (UniProt)
4E-BP1-P ProteinQ13541 (UniProt)
MEK1:ERK-1 ComplexREACT_5539 (Reactome)
Activated RAF1

complex:MEK2

ComplexREACT_4223 (Reactome)
phospho-ERK-1:

MEK1

ComplexREACT_2796 (Reactome)
RAF activation PathwayREACT_2077 (Reactome)
Activated ERK1 ProteinP27361 (UniProt)
Crk:SOS:IRS-P ComplexREACT_2957 (Reactome)
phospho-ERK-1

dimer

ComplexREACT_3932 (Reactome)
V-ATPase ComplexREACT_24332 (Reactome)
phospho-ERK-1

dimer

ComplexREACT_3152 (Reactome)
PIP3:PDK1 complex ComplexREACT_5409 (Reactome)
IRS ProteinREACT_2507 (Reactome)
PKB regulator ProteinREACT_5778 (Reactome)
IRS:activated insulin

receptor

ComplexREACT_3393 (Reactome)
TSC2-1 ProteinP49815-1 (UniProt)
phospho-IRS:

activated insulin receptor

ComplexREACT_4013 (Reactome)
TSC1:TSC2 ComplexREACT_7850 (Reactome)
phospho-IRS ProteinREACT_4422 (Reactome)
Rheb:GDP ComplexREACT_7464 (Reactome)
phospho-IRS-

1/2

ProteinREACT_4523 (Reactome)
mTOR ProteinP42345 (UniProt)
GRB2:SOS:IRS-P ComplexREACT_3414 (Reactome)
Raptor ProteinREACT_7195 (Reactome)
activated insulin

receptor

ComplexREACT_4836 (Reactome)
S6K1 ProteinP23443 (UniProt)
H+ Metabolite15378 (ChEBI)
Phosphorylated

Raptor

ProteinQ8N122-1 (UniProt)
phospho-insulin

receptor

ComplexREACT_3809 (Reactome)
Phosphorylated 40S

small ribosomal protein 6

ProteinP62753 (UniProt)
insulin ComplexREACT_3655 (Reactome)
eEF2K-P ProteinO00418 (UniProt)
Orthophosphate Metabolite18367 (ChEBI)
MEK2:ERK-2 ComplexREACT_5435 (Reactome)
insulin receptor ComplexREACT_3854 (Reactome)
Activated ERK2 ProteinP28482 (UniProt)
protein tyrosine

phosphatase

UnknownREACT_3980 (Reactome)
phospho-ERK-2

dimer

ComplexREACT_5046 (Reactome)
PI3K ComplexREACT_4240 (Reactome)
eIF4G-P ProteinQ04637 (UniProt)
phospho-IRS:PI3K ComplexREACT_3175 (Reactome)
eIF4B-P ProteinP23588 (UniProt)
Phosphatidyl-

myo-inositol 4,5- bisphosphate

Unknown18348 (ChEBI)
eIF4E:4E-BP1-P ComplexREACT_7838 (Reactome)
Phosphatidylinositol-

3,4,5-trisphosphate

Unknown16618 (ChEBI)
eIF4E ProteinP06730 (UniProt)
Activated PI3K UnknownREACT_9165 (Reactome)
Activated RAF1

complex:MEK1

ComplexREACT_4256 (Reactome)
3',5'-Cyclic AMP Metabolite17489 (ChEBI)
phospho_MEK1 ProteinREACT_3339 (Reactome)
H2O Metabolite15377 (ChEBI)
phospho-Cdc2 (Thr

161)

ProteinP06493 (UniProt)
AMP Metabolite16027 (ChEBI)
phospho-SOS ProteinQ07889 (UniProt)
Phosphorylated

PDE3B

ProteinQ13370 (UniProt)
GRB2:IRS-P ComplexREACT_5160 (Reactome)
Phosphodiesterase

3B

ProteinQ13370 (UniProt)
Crk:IRS-P ComplexREACT_4822 (Reactome)
PIP3:Phosphorylated

PKB complex

ComplexREACT_3373 (Reactome)
GRB10:INSR ComplexREACT_5054 (Reactome)
PDK1 ProteinO15530 (UniProt)
IDA UnknownREACT_2385 (Reactome)

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