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
BRITE hierarchy
Pathway map
oaa04910  Insulin signaling pathway

Ortholog table
Ornithorhynchus anatinus (platypus) [GN:oaa]
100079104  INSR; insulin receptor [KO:K04527] [EC:]
100080187  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
100084726  phosphatidylinositol 3-kinase regulatory subunit alpha-like [KO:K02649]
100082075  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
100086270  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
100073788  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
100074273  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
100089083  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:]
100083320  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
100081473  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
100092089  glycogen synthase kinase-3 beta-like [KO:K03083] [EC:]
100074446  GYS1; glycogen synthase 1 [KO:K00693] [EC:]
100074395  PPP1CC; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:]
100078635  PPP1CB; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:]
100079515  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
100080024  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
100075652  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100091257  protein phosphatase 1 regulatory subunit 3C-like [KO:K07189]
103171070  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
100075695  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
100088260  PHKG1; phosphorylase kinase catalytic subunit gamma 1 [KO:K00871] [EC:]
100093441  PHKG2; phosphorylase kinase catalytic subunit gamma 2 [KO:K00871] [EC:]
100075998  PHKB; phosphorylase kinase regulatory subunit beta [KO:K07190]
100083592  PHKA2; phosphorylase kinase regulatory subunit alpha 2 [KO:K07190]
100092559  PHKA1; phosphorylase kinase regulatory subunit alpha 1 [KO:K07190]
100075369  CALM1; calmodulin 1 [KO:K02183]
100083509  calmodulin [KO:K02183]
100085837  CALML4; calmodulin like 4 [KO:K02183]
100084785  PYGL; glycogen phosphorylase L [KO:K00688] [EC:]
100088979  cGMP-inhibited 3',5'-cyclic phosphodiesterase B-like [KO:K13296] [EC:]
100078846  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
100088079  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:]
100078086  PRKAR2B; protein kinase cAMP-dependent type II regulatory subunit beta [KO:K04739]
100078562  PRKAR1A; protein kinase cAMP-dependent type I regulatory subunit alpha [KO:K04739]
100089779  protein kinase C zeta type-like [KO:K18952] [EC:]
100077834  PRKCI; protein kinase C iota type [KO:K06069] [EC:]
100086580  protein kinase C iota type-like [KO:K06069] [EC:]
100073670  flotillin-2-like [KO:K07192]
100090126  SH2B2; SH2B adapter protein 2 [KO:K07193]
100074518  SORBS1; sorbin and SH3 domain containing 1 [KO:K06086]
100091424  E3 ubiquitin-protein ligase CBL-like [KO:K04707] [EC:]
100089052  CBLB; Cbl proto-oncogene B [KO:K22517] [EC:]
100092854  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
100076081  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
100075047  RAPGEF1; Rap guanine nucleotide exchange factor 1 [KO:K06277]
100091523  exocyst complex component 7-like [KO:K07195]
100074517  TRIP10; thyroid hormone receptor interactor 10 [KO:K07196]
100079611  SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
100078541  ACACA; acetyl-CoA carboxylase alpha [KO:K11262] [EC:]
100076923  ACACB; acetyl-CoA carboxylase beta [KO:K01946] [EC:]
100091954  fatty acid synthase-like [KO:K00665] [EC:]
100088018  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:]
100085443  HK1; hexokinase 1 [KO:K00844] [EC:]
100091176  GCK; glucokinase [KO:K12407] [EC:]
100075352  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:]
100083731  5'-AMP-activated protein kinase subunit beta-2-like [KO:K07199]
100082459  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
100082288  FOXO1; forkhead box O1 [KO:K07201]
100081496  PPARGC1A; PPARG coactivator 1 alpha [KO:K07202]
100083297  G6PC2; glucose-6-phosphatase catalytic subunit 2 [KO:K01084] [EC:]
100088723  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:]
100081530  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:]
100092809  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:]
100073969  PCK1; phosphoenolpyruvate carboxykinase 1 [KO:K01596] [EC:]
100088404  PCK2; phosphoenolpyruvate carboxykinase 2, mitochondrial [KO:K01596] [EC:]
100079751  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:]
100087780  ribosomal protein S6 kinase beta-2-like [KO:K04688] [EC:]
100078852  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:]
100074741  RPS6; ribosomal protein S6 [KO:K02991]
100084037  EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
100082898  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
100084131  eukaryotic translation initiation factor 4E-like [KO:K03259]
100090683  eukaryotic translation initiation factor 4E-like [KO:K03259]
100080641  TSC1; tuberous sclerosis 1 [KO:K07206]
100086661  TSC2; tuberous sclerosis 2 [KO:K07207]
100082482  RHEB; Ras homolog enriched in brain [KO:K07208]
100081397  SHC2; SHC adaptor protein 2 [KO:K17447]
100075806  GRB2; growth factor receptor bound protein 2 [KO:K04364]
100079295  GRAP; GRB2-related adaptor protein [KO:K04364]
100084645  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
100078989  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
100085430  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
100084423  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:]
100086380  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:]
100089456  RAF proto-oncogene serine/threonine-protein kinase-like [KO:K04366] [EC:]
100080362  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
100087942  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
100085480  mitogen-activated protein kinase 1-like [KO:K04371] [EC:]
100086487  mitogen-activated protein kinase 3-like [KO:K04371] [EC:]
100086826  MAP kinase-interacting serine/threonine-protein kinase 2-like [KO:K04372] [EC:]
100079417  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100090302  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100091294  suppressor of cytokine signaling 4-like [KO:K04697]
100077166  PTPN1; protein tyrosine phosphatase, non-receptor type 1 [KO:K05696] [EC:]
100078392  PTPRF; protein tyrosine phosphatase, receptor type F [KO:K05695] [EC:]
100073424  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
100076033  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
100082590  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
100078925  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:]
100088229  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like [KO:K15909] [EC:]
C00031  D-Glucose
C00369  Starch
C00575  3',5'-Cyclic AMP
C05981  Phosphatidylinositol-3,4,5-trisphosphate
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)
KO pathway

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