Entry |
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Name |
Insulin signaling pathway
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Description |
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.
Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
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Class |
Organismal Systems; Endocrine system
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Pathway map |

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Disease |
H00942 | Rabson-Mendenhall syndrome |
H01154 | Wolff-Parkinson-White (WPW) syndrome |
H01251 | Focal cortical dysplasia of Taylor |
H01267 | Familial hyperinsulinemic hypoglycemia |
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Reference |
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Authors |
Ogawa W, Kasuga M. |
Title |
[Mechanism of insulin action and diabetes mellitus] |
Journal |
Seikagaku 75:1332-44 (2003) |
Reference |
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Authors |
Bevan P. |
Title |
Insulin signalling. |
Journal |
J Cell Sci 114:1429-30 (2001) |
Reference |
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Authors |
Kanzaki M, Pessin JE. |
Title |
Insulin signaling: GLUT4 vesicles exit via the exocyst. |
Journal |
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Reference |
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Authors |
Moodie SA, Alleman-Sposeto J, Gustafson TA. |
Title |
Identification of the APS protein as a novel insulin receptor substrate. |
Journal |
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Reference |
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Authors |
Gual P, Le Marchand-Brustel Y, Tanti JF. |
Title |
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. |
Journal |
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Reference |
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Authors |
Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ. |
Title |
Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. |
Journal |
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Reference |
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Authors |
Saltiel AR, Kahn CR. |
Title |
Insulin signalling and the regulation of glucose and lipid metabolism. |
Journal |
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Reference |
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Authors |
Inoki K, Corradetti MN, Guan KL. |
Title |
Dysregulation of the TSC-mTOR pathway in human disease. |
Journal |
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Reference |
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Authors |
Ruggero D, Sonenberg N. |
Title |
The Akt of translational control. |
Journal |
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Reference |
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Authors |
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. |
Title |
Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. |
Journal |
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Reference |
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Authors |
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. |
Title |
Phosphorylation and activation of p70s6k by PDK1. |
Journal |
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Reference |
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Authors |
Ogawa W, Matozaki T, Kasuga M. |
Title |
Role of binding proteins to IRS-1 in insulin signalling. |
Journal |
Mol Cell Biochem 182:13-22 (1998) |
Reference |
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Authors |
Ceresa BP, Pessin JE. |
Title |
Insulin regulation of the Ras activation/inactivation cycle. |
Journal |
Mol Cell Biochem 182:23-9 (1998) |
Reference |
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Authors |
Pollak MN, Schernhammer ES, Hankinson SE. |
Title |
Insulin-like growth factors and neoplasia. |
Journal |
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Reference |
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Authors |
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. |
Title |
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. |
Journal |
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Reference |
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Authors |
Ferre P, Foufelle F |
Title |
SREBP-1c transcription factor and lipid homeostasis: clinical perspective. |
Journal |
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Reference |
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Authors |
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB |
Title |
SREBPs: the crossroads of physiological and pathological lipid homeostasis. |
Journal |
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Reference |
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Authors |
Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S |
Title |
The lipid phosphatase SHIP2 controls insulin sensitivity. |
Journal |
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Reference |
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Authors |
Backers K, Blero D, Paternotte N, Zhang J, Erneux C |
Title |
The termination of PI3K signalling by SHIP1 and SHIP2 inositol 5-phosphatases. |
Journal |
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Related pathway |
map04070 | Phosphatidylinositol signaling system |
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KO pathway |
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