Entry
Name
Insulin signaling pathway - Ornithorhynchus anatinus (platypus)
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.
Class
Organismal Systems; Endocrine system
BRITE hierarchy
Pathway map
Ortholog table
Organism
Ornithorhynchus anatinus (platypus) [GN:
oaa ]
Gene
114808089 LOW QUALITY PROTEIN: insulin receptor substrate 1-like [KO:K17445 ]
100080187 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649 ]
100082075 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649 ]
103167126 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649 ]
100086270 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
100073788 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
100074273 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
100074395 PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X3 [KO:K06269 ] [EC:3.1.3.16 ]
100092226 PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X1 [KO:K06269 ] [EC:3.1.3.16 ]
100079515 PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189 ]
114816130 PPP1R3E; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3E [KO:K07189 ]
100075695 PPP1R3F; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3F [KO:K17453 ]
100093441 PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871 ] [EC:2.7.11.19 ]
100092559 PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190 ]
100075998 PHKB; phosphorylase b kinase regulatory subunit beta isoform X3 [KO:K07190 ]
100083592 PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190 ]
100078086 PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739 ]
100078562 PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X1 [KO:K04739 ]
100080856 PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739 ]
100080978 PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739 ]
100091317 SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191 ]
100074518 SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086 ]
100075047 RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X3 [KO:K06277 ]
100076316 RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194 ]
100083731 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199 ]
100093063 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
100082459 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X3 [KO:K07200 ]
100080957 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200 ]
100082856 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
100081496 PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202 ]
100084037 EIF4EBP1; LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205 ]
100082898 EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259 ]
100090683 EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X2 [KO:K03259 ]
100088229 INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909 ] [EC:3.1.3.86 ]
Compound
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference
Authors
Ogawa W, Kasuga M.
Title
[Mechanism of insulin action and diabetes mellitus]
Journal
Seikagaku 75:1332-44 (2003)
Reference
Authors
Bevan P.
Title
Insulin signalling.
Journal
J Cell Sci 114:1429-30 (2001)
Reference
Authors
Kanzaki M, Pessin JE.
Title
Insulin signaling: GLUT4 vesicles exit via the exocyst.
Journal
Reference
Authors
Moodie SA, Alleman-Sposeto J, Gustafson TA.
Title
Identification of the APS protein as a novel insulin receptor substrate.
Journal
Reference
Authors
Gual P, Le Marchand-Brustel Y, Tanti JF.
Title
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
Journal
Reference
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
Reference
Authors
Saltiel AR, Kahn CR.
Title
Insulin signalling and the regulation of glucose and lipid metabolism.
Journal
Reference
Authors
Inoki K, Corradetti MN, Guan KL.
Title
Dysregulation of the TSC-mTOR pathway in human disease.
Journal
Reference
Authors
Ruggero D, Sonenberg N.
Title
The Akt of translational control.
Journal
Reference
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
Reference
Authors
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G.
Title
Phosphorylation and activation of p70s6k by PDK1.
Journal
Reference
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
Authors
Ceresa BP, Pessin JE.
Title
Insulin regulation of the Ras activation/inactivation cycle.
Journal
Mol Cell Biochem 182:23-9 (1998)
Reference
Authors
Pollak MN, Schernhammer ES, Hankinson SE.
Title
Insulin-like growth factors and neoplasia.
Journal
Reference
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
Reference
Authors
Ferre P, Foufelle F
Title
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
Journal
Reference
Authors
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB
Title
SREBPs: the crossroads of physiological and pathological lipid homeostasis.
Journal
Reference
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
Reference
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
Related pathway
oaa04070 Phosphatidylinositol signaling system
KO pathway
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