KEGG   PATHWAY: oaa04910
Entry
oaa04910                    Pathway                                
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
Pathway map
oaa04910  Insulin signaling pathway
oaa04910

Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
114810063  INS; insulin [KO:K04526]
100079104  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
103170729  IRS1; insulin receptor substrate 1 [KO:K16172]
114805830  IRS2; insulin receptor substrate 2 [KO:K07187]
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]
100089083  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100083320  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100081473  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100090267  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100092089  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100074446  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
107547250  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100074395  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X3 [KO:K06269] [EC:3.1.3.16]
100078635  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [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]
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]
103166670  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [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]
100088260  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
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]
100075369  CALM1; calmodulin-1 [KO:K02183]
100083509  CALM2; calmodulin-2 [KO:K02183]
100085837  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
103165382  calmodulin-A-like [KO:K02183]
114812128  CALM3; calmodulin-3 [KO:K02183]
114816270  CALML3; calmodulin-like protein 3 [KO:K02183]
100084785  PYGL; LOW QUALITY PROTEIN: glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100084973  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100085834  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
100088979  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
100078846  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100088079  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
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]
103167455  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
100089779  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100077834  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
100091317  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100073670  FLOT2; flotillin-2 isoform X1 [KO:K07192]
114807979  FLOT1; flotillin-1 [KO:K07192]
100090126  SH2B2; LOW QUALITY PROTEIN: SH2B adapter protein 2 [KO:K07193]
100074518  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
100091424  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
100089052  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
100092854  CRK; adapter molecule crk isoform X1 [KO:K04438]
100076081  CRKL; crk-like protein [KO:K04438]
100075047  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X3 [KO:K06277]
100076316  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
100091523  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
100079611  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
100078541  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100076923  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100091954  FASN; LOW QUALITY PROTEIN: fatty acid synthase [KO:K00665] [EC:2.3.1.85]
114808131  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
100088018  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
100085443  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
100074718  HK2; LOW QUALITY PROTEIN: hexokinase-2 [KO:K00844] [EC:2.7.1.1]
100079843  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
100091176  hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
114815128  LOW QUALITY PROTEIN: hexokinase-4-like [KO:K12407] [EC:2.7.1.2]
100075352  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100088284  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
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]
100082288  FOXO1; forkhead box protein O1 [KO:K07201]
100081496  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
100083297  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
100088723  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100092475  G6PC1; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100081530  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
100092809  fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
100073969  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100088404  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100079751  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100090165  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
100087780  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100078852  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100074741  RPS6; 40S ribosomal protein S6 [KO:K02991]
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]
100084131  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
100090683  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X2 [KO:K03259]
100080641  TSC1; hamartin isoform X4 [KO:K07206]
100086661  TSC2; tuberin isoform X1 [KO:K07207]
100082482  RHEB; GTP-binding protein Rheb [KO:K07208]
114810030  BAD; bcl2-associated agonist of cell death [KO:K02158]
114808180  SHC1; SHC-transforming protein 1 [KO:K06279]
100081397  SHC2; SHC-transforming protein 2 [KO:K17447]
100075806  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100084645  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100078989  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
114809992  HRAS; GTPase HRas [KO:K02833]
100085430  KRAS; GTPase KRas isoform X1 [KO:K07827]
100074671  NRAS; GTPase NRas [KO:K07828]
100084423  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
100086380  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
100089456  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100080362  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100087942  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100085480  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100086487  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100086826  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
100681770  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
100681469  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
114809105  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
114816636  suppressor of cytokine signaling 1-like [KO:K04694]
100079417  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
100090302  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100086717  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
100077166  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X3 [KO:K05696] [EC:3.1.3.48]
100078392  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
100073424  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100076033  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
100082590  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100078925  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100088229  INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
100093027  INPP5A; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
Compound
C00031  D-Glucose
C00369  Starch
C00575  3',5'-Cyclic AMP
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:14635525
  Authors
Ogawa W, Kasuga M.
  Title
[Mechanism of insulin action and diabetes mellitus]
  Journal
Seikagaku 75:1332-44 (2003)
Reference
PMID:11282018
  Authors
Bevan P.
  Title
Insulin signalling.
  Journal
J Cell Sci 114:1429-30 (2001)
Reference
PMID:12867054
  Authors
Kanzaki M, Pessin JE.
  Title
Insulin signaling: GLUT4 vesicles exit via the exocyst.
  Journal
Curr Biol 13:R574-6 (2003)
DOI:10.1016/S0960-9822(03)00478-0
Reference
PMID:10196204
  Authors
Moodie SA, Alleman-Sposeto J, Gustafson TA.
  Title
Identification of the APS protein as a novel insulin receptor substrate.
  Journal
J Biol Chem 274:11186-93 (1999)
DOI:10.1074/jbc.274.16.11186
Reference
PMID:15733744
  Authors
Gual P, Le Marchand-Brustel Y, Tanti JF.
  Title
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
  Journal
Biochimie 87:99-109 (2005)
DOI:10.1016/j.biochi.2004.10.019
Reference
PMID:9748166
  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
Science 281:2042-5 (1998)
DOI:10.1126/science.281.5385.2042
Reference
PMID:11742412
  Authors
Saltiel AR, Kahn CR.
  Title
Insulin signalling and the regulation of glucose and lipid metabolism.
  Journal
Nature 414:799-806 (2001)
DOI:10.1038/414799a
Reference
PMID:15624019
  Authors
Inoki K, Corradetti MN, Guan KL.
  Title
Dysregulation of the TSC-mTOR pathway in human disease.
  Journal
Nat Genet 37:19-24 (2005)
DOI:10.1038/ng1494
Reference
PMID:16288289
  Authors
Ruggero D, Sonenberg N.
  Title
The Akt of translational control.
  Journal
Oncogene 24:7426-34 (2005)
DOI:10.1038/sj.onc.1209098
Reference
PMID:10567225
  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
Biochem J 344 Pt 2:427-31 (1999)
DOI:10.1042/bj3440427
Reference
PMID:9445476
  Authors
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G.
  Title
Phosphorylation and activation of p70s6k by PDK1.
  Journal
Science 279:707-10 (1998)
DOI:10.1126/science.279.5351.707
Reference
PMID:9609110
  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
PMID:9609111
  Authors
Ceresa BP, Pessin JE.
  Title
Insulin regulation of the Ras activation/inactivation cycle.
  Journal
Mol Cell Biochem 182:23-9 (1998)
Reference
PMID:15229476
  Authors
Pollak MN, Schernhammer ES, Hankinson SE.
  Title
Insulin-like growth factors and neoplasia.
  Journal
Nat Rev Cancer 4:505-18 (2004)
DOI:10.1038/nrc1387
Reference
PMID:9346240
  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
Cell 91:231-41 (1997)
DOI:10.1016/S0092-8674(00)80405-5
Reference
PMID:17344645
  Authors
Ferre P, Foufelle F
  Title
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
  Journal
Horm Res 68:72-82 (2007)
DOI:10.1159/000100426
Reference
PMID:18291668
  Authors
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB
  Title
SREBPs: the crossroads of physiological and pathological lipid homeostasis.
  Journal
Trends Endocrinol Metab 19:65-73 (2008)
DOI:10.1016/j.tem.2007.10.009
Reference
PMID:11343120
  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
Nature 409:92-7 (2001)
DOI:10.1038/35051094
Reference
PMID:12791379
  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
Adv Enzyme Regul 43:15-28 (2003)
DOI:10.1016/S0065-2571(02)00043-2
Related
pathway
oaa00010  Glycolysis / Gluconeogenesis
oaa00061  Fatty acid biosynthesis
oaa00500  Starch and sucrose metabolism
oaa04010  MAPK signaling pathway
oaa04070  Phosphatidylinositol signaling system
oaa04210  Apoptosis
KO pathway
ko04910   

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Genome (1)   
   KEGG GENOME (1)   
Gene (135)   
   KEGG GENES (135)   
All databases (136)   

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