KEGG   PATHWAY: oaa04910Help
oaa04910                    Pathway                                

Insulin signaling pathway - Ornithorhynchus anatinus (platypus)
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.
Organismal Systems; Endocrine system
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Insulin signaling pathway

All organismsOrtholog table
Ornithorhynchus anatinus (platypus) [GN:oaa]
INSR; insulin receptor [KO:K04527] [EC:]
phosphoinositide 3-kinase regulatory subunit 5-like; K02649 phosphoinositide-3-kinase, regulatory subunit [KO:K02649]
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
phosphatidylinositol 3-kinase regulatory subunit alpha-like; K02649 phosphoinositide-3-kinase, regulatory subunit [KO:K02649]
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:]
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:]
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:]
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:]
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:]
AKT3; v-akt murine thymoma viral oncogene homolog 3 [KO:K04456] [EC:]
RAC-alpha serine/threonine-protein kinase; K04456 RAC serine/threonine-protein kinase [EC:] [KO:K04456] [EC:]
glycogen synthase kinase-3 beta-like; K03083 glycogen synthase kinase 3 beta [EC:] [KO:K03083] [EC:]
GYS1; glycogen synthase 1 (muscle) [KO:K00693] [EC:]
PPP1CC; protein phosphatase 1, catalytic subunit, gamma isozyme [KO:K06269] [EC:]
PPP1CB; protein phosphatase 1, catalytic subunit, beta isozyme [KO:K06269] [EC:]
PPP1R3B; protein phosphatase 1, regulatory subunit 3B [KO:K07189]
PPP1R3A; protein phosphatase 1, regulatory subunit 3A [KO:K07189]
PPP1R3C; protein phosphatase 1, regulatory subunit 3C [KO:K07189]
protein phosphatase 1 regulatory subunit 3C-like; K07189 protein phosphatase 1 regulatory subunit 3A/B/C/D/E [KO:K07189]
PPP1R3D; protein phosphatase 1, regulatory subunit 3D [KO:K07189]
PPP1R3F; protein phosphatase 1, regulatory subunit 3F [KO:K17453]
PHKG1; phosphorylase kinase, gamma 1 (muscle) [KO:K00871] [EC:]
PHKG2; phosphorylase kinase, gamma 2 (testis) [KO:K00871] [EC:]
PHKB; phosphorylase kinase, beta [KO:K07190]
PHKA2; phosphorylase kinase, alpha 2 (liver) [KO:K07190]
PHKA1; phosphorylase kinase, alpha 1 (muscle) [KO:K07190]
CALM1; calmodulin 1 (phosphorylase kinase, delta) [KO:K02183]
uncharacterized LOC100085924; K02183 calmodulin [KO:K02183]
neo-calmodulin; K02183 calmodulin [KO:K02183]
PYGL; phosphorylase, glycogen, liver [KO:K00688] [EC:]
cGMP-inhibited 3'; K13296 cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:] [KO:K13296] [EC:]
PRKACB; protein kinase, cAMP-dependent, catalytic, beta [KO:K04345] [EC:]
cAMP-dependent protein kinase catalytic subunit alpha-like; K04345 protein kinase A [EC:] [KO:K04345] [EC:]
PRKAR2B; protein kinase, cAMP-dependent, regulatory, type II, beta [KO:K04739]
PRKAR1A; protein kinase, cAMP-dependent, regulatory, type I, alpha [KO:K04739]
protein kinase C zeta type-like; K18952 atypical protein kinase C zeta type [EC:] [KO:K18952] [EC:]
PRKCI; protein kinase C iota type [KO:K06069] [EC:]
protein kinase C iota type-like; K06069 atypical protein kinase C iota type [EC:] [KO:K06069] [EC:]
flotillin-2-like; K07192 flotillin [KO:K07192]
SH2B2; SH2B adaptor protein 2 [KO:K07193]
SORBS1; sorbin and SH3 domain containing 1 [KO:K06086]
E3 ubiquitin-protein ligase CBL-like; K04707 E3 ubiquitin-protein ligase CBL [EC:] [KO:K04707] [EC:]
CBLB; Cbl proto-oncogene B, E3 ubiquitin protein ligase [KO:K04707] [EC:]
CRK; v-crk avian sarcoma virus CT10 oncogene homolog [KO:K04438]
CRKL; v-crk avian sarcoma virus CT10 oncogene homolog-like [KO:K04438]
RAPGEF1; Rap guanine nucleotide exchange factor (GEF) 1 [KO:K06277]
exocyst complex component 7-like; K07195 exocyst complex component 7 [KO:K07195]
TRIP10; thyroid hormone receptor interactor 10 [KO:K07196]
SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
ACACA; acetyl-CoA carboxylase alpha [KO:K11262] [EC:]
ACACB; acetyl-CoA carboxylase beta [KO:K01946] [EC:]
fatty acid synthase-like; K00665 fatty acid synthase, animal type [EC:] [KO:K00665] [EC:]
pyruvate kinase PKLR-like; K12406 pyruvate kinase isozymes R/L [EC:] [KO:K12406] [EC:]
HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:]
HK1; hexokinase 1 [KO:K00844] [EC:]
GCK; glucokinase (hexokinase 4) [KO:K12407] [EC:]
PRKAA1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:]
5'-AMP-activated protein kinase subunit beta-2-like; K07199 5'-AMP-activated protein kinase, regulatory beta subunit [KO:K07199]
PRKAG2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
FOXO1; forkhead box O1 [KO:K07201]
PPARGC1A; peroxisome proliferator-activated receptor gamma, coactivator 1 alpha [KO:K07202]
G6PC2; glucose-6-phosphatase, catalytic, 2 [KO:K01084] [EC:]
G6PC3; glucose 6 phosphatase, catalytic, 3 [KO:K01084] [EC:]
fructose-1; K03841 fructose-1,6-bisphosphatase I [EC:] [KO:K03841] [EC:]
fructose-1; K03841 fructose-1,6-bisphosphatase I [EC:] [KO:K03841] [EC:]
PCK1; phosphoenolpyruvate carboxykinase 1 (soluble) [KO:K01596] [EC:]
PCK2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:]
MTOR; mechanistic target of rapamycin (serine/threonine kinase) [KO:K07203] [EC:]
RPTOR; regulatory-associated protein of mTOR [KO:K07204]
ribosomal protein S6 kinase beta-2-like; K04688 p70 ribosomal S6 kinase [EC:] [KO:K04688] [EC:]
RPS6KB1; ribosomal protein S6 kinase, 70kDa, polypeptide 1 [KO:K04688] [EC:]
RPS6; ribosomal protein S6 [KO:K02991]
EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
eukaryotic translation initiation factor 4E type 2-like; K03259 translation initiation factor 4E [KO:K03259]
eukaryotic translation initiation factor 4E-like; K03259 translation initiation factor 4E [KO:K03259]
eukaryotic translation initiation factor 4E-like; K03259 translation initiation factor 4E [KO:K03259]
TSC1; tuberous sclerosis 1 [KO:K07206]
TSC2; tuberous sclerosis 2 [KO:K07207]
RHEB; Ras homolog enriched in brain [KO:K07208]
SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
GRAP; GRB2-related adaptor protein [KO:K04364]
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
ARAF; v-raf murine sarcoma 3611 viral oncogene homolog [KO:K08845] [EC:]
BRAF; v-raf murine sarcoma viral oncogene homolog B [KO:K04365] [EC:]
RAF proto-oncogene serine/threonine-protein kinase-like; K04366 RAF proto-oncogene serine/threonine-protein kinase [EC:] [KO:K04366] [EC:]
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
dual specificity mitogen-activated protein kinase kinase 2; K04369 mitogen-activated protein kinase kinase 2 [EC:] [KO:K04369] [EC:]
mitogen-activated protein kinase 1-like; K04371 mitogen-activated protein kinase 1/3 [EC:] [KO:K04371] [EC:]
mitogen-activated protein kinase 3-like; K04371 mitogen-activated protein kinase 1/3 [EC:] [KO:K04371] [EC:]
MAP kinase-interacting serine/threonine-protein kinase 2-like; K04372 MAP kinase interacting serine/threonine kinase [EC:] [KO:K04372] [EC:]
suppressor of cytokine signaling 2-like; K04694 suppressor of cytokine signaling 1 [KO:K04694]
SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
suppressor of cytokine signaling 4-like; K04697 suppressor of cytokine signaling 4 [KO:K04697]
PTPN1; protein tyrosine phosphatase, non-receptor type 1 [KO:K05696] [EC:]
PTPRF; protein tyrosine phosphatase, receptor type, F [KO:K05695] [EC:]
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:]
phosphatidylinositol 3; K15909 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 [EC:] [KO:K15909] [EC:]
3',5'-Cyclic AMP
Ogawa W, Kasuga M.
[Mechanism of insulin action and diabetes mellitus]
Seikagaku 75:1332-44 (2003)
Bevan P.
Insulin signalling.
J Cell Sci 114:1429-30 (2001)
Kanzaki M, Pessin JE.
Insulin signaling: GLUT4 vesicles exit via the exocyst.
Curr Biol 13:R574-6 (2003)
Moodie SA, Alleman-Sposeto J, Gustafson TA.
Identification of the APS protein as a novel insulin receptor substrate.
J Biol Chem 274:11186-93 (1999)
Gual P, Le Marchand-Brustel Y, Tanti JF.
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
Biochimie 87:99-109 (2005)
Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ.
Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.
Science 281:2042-5 (1998)
Saltiel AR, Kahn CR.
Insulin signalling and the regulation of glucose and lipid metabolism.
Nature 414:799-806 (2001)
Inoki K, Corradetti MN, Guan KL.
Dysregulation of the TSC-mTOR pathway in human disease.
Nat Genet 37:19-24 (2005)
Ruggero D, Sonenberg N.
The Akt of translational control.
Oncogene 24:7426-34 (2005)
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR.
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.
Biochem J 344 Pt 2:427-31 (1999)
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G.
Phosphorylation and activation of p70s6k by PDK1.
Science 279:707-10 (1998)
Ogawa W, Matozaki T, Kasuga M.
Role of binding proteins to IRS-1 in insulin signalling.
Mol Cell Biochem 182:13-22 (1998)
Ceresa BP, Pessin JE.
Insulin regulation of the Ras activation/inactivation cycle.
Mol Cell Biochem 182:23-9 (1998)
Pollak MN, Schernhammer ES, Hankinson SE.
Insulin-like growth factors and neoplasia.
Nat Rev Cancer 4:505-18 (2004)
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
Cell 91:231-41 (1997)
Ferre P, Foufelle F
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
Horm Res 68:72-82 (2007)
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB
SREBPs: the crossroads of physiological and pathological lipid homeostasis.
Trends Endocrinol Metab 19:65-73 (2008)
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
The lipid phosphatase SHIP2 controls insulin sensitivity.
Nature 409:92-7 (2001)
Backers K, Blero D, Paternotte N, Zhang J, Erneux C
The termination of PI3K signalling by SHIP1 and SHIP2 inositol 5-phosphatases.
Adv Enzyme Regul 43:15-28 (2003)
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