KEGG   PATHWAY: oor04910
Entry
oor04910                    Pathway                                
Name
Insulin signaling pathway - Orcinus orca (killer whale)
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
oor04910  Insulin signaling pathway
oor04910

Organism
Orcinus orca (killer whale) [GN:oor]
Gene
101278494  INS; insulin [KO:K04526]
101283355  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
101271463  IRS1; insulin receptor substrate 1 [KO:K16172]
101276950  IRS2; insulin receptor substrate 2 isoform X2 [KO:K07187]
101279800  insulin receptor substrate 1-like isoform X1 [KO:K17445]
101290244  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
101277568  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101285437  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101281352  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
101278075  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101278974  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
101283011  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101270868  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101272095  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101288103  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101273316  AKT1; RAC-alpha serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101283259  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
101287552  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
101284496  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
101285623  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
101280558  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
101286983  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
101269325  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X5 [KO:K07189]
101273975  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
101283906  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
101288699  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
101280098  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
101281573  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
101270202  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
101270022  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X7 [KO:K07190]
101275570  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X2 [KO:K07190]
101288789  PHKB; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
101278649  CALML6; calmodulin-like protein 6 [KO:K02183]
101273078  CALM2; calmodulin-2 [KO:K02183]
101285814  CALM1; calmodulin-1 [KO:K02183]
101279979  CALM3; calmodulin-3 [KO:K02183]
101282017  calmodulin-alpha-like isoform X1 [KO:K02183]
105748632  LOW QUALITY PROTEIN: myosin light chain 1, skeletal muscle isoform-like [KO:K02183]
101284096  calmodulin-1-like [KO:K02183]
125961823  calmodulin-1-like [KO:K02183]
125961824  calmodulin-1-like [KO:K02183]
125961825  calmodulin-1-like [KO:K02183]
125961826  calmodulin-1-like [KO:K02183]
125961827  calmodulin-1-like [KO:K02183]
125961828  calmodulin-1-like [KO:K02183]
101269285  PYGL; glycogen phosphorylase, liver form isoform X2 [KO:K00688] [EC:2.4.1.1]
101279103  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
101287131  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
101270317  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
101272376  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101273911  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101287954  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
101279316  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
101281541  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
101286959  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
101277193  LIPE; LOW QUALITY PROTEIN: hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
101283233  PRKCZ; protein kinase C zeta type isoform X3 [KO:K18952] [EC:2.7.11.13]
101287805  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
101273257  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X2 [KO:K07191]
101271003  FLOT1; flotillin-1 [KO:K07192]
101272997  FLOT2; flotillin-2 isoform X1 [KO:K07192]
101270777  SH2B2; SH2B adapter protein 2 isoform X3 [KO:K07193]
101282715  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
101270049  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
101280577  CBLB; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
101270546  CRKL; crk-like protein [KO:K04438]
101284062  CRK; adapter molecule crk isoform X1 [KO:K04438]
101281077  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
101278777  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
101277598  EXOC7; exocyst complex component 7 isoform X11 [KO:K07195]
101281919  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
101272079  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
101277103  ACACA; acetyl-CoA carboxylase 1 isoform X4 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101272632  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101279575  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
101290268  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
101278255  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
101281461  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
101271458  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
101271708  HKDC1; hexokinase HKDC1 isoform X2 [KO:K00844] [EC:2.7.1.1]
101286839  GCK; hexokinase-4 isoform X6 [KO:K12407] [EC:2.7.1.2]
101287451  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101290391  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
101270605  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
101289338  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101286740  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
101269890  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
101288264  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
101285637  FOXO1; forkhead box protein O1 [KO:K07201]
101270017  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X2 [KO:K07202]
101281224  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
101288353  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
101283146  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
101285491  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
101285747  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
101275401  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
101284360  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
101284249  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
101290397  RPTOR; regulatory-associated protein of mTOR isoform X5 [KO:K07204]
101286642  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
101283084  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101274774  RPS6; 40S ribosomal protein S6 [KO:K02991]
101273702  40S ribosomal protein S6-like [KO:K02991]
101274788  40S ribosomal protein S6-like [KO:K02991]
117196421  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
101277165  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101287292  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101282865  EIF4E; eukaryotic translation initiation factor 4E isoform X4 [KO:K03259]
101281614  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101277344  eukaryotic translation initiation factor 4E-like [KO:K03259]
101275677  TSC1; hamartin isoform X1 [KO:K07206]
101276336  TSC2; tuberin isoform X9 [KO:K07207]
101286490  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
101274967  BAD; bcl2-associated agonist of cell death [KO:K02158]
101276908  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
101275665  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
101280480  SHC3; SHC-transforming protein 3 isoform X2 [KO:K17448]
101289594  SHC4; SHC-transforming protein 4 isoform X4 [KO:K17449]
101271441  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101286587  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105748221  LOW QUALITY PROTEIN: son of sevenless homolog 2-like [KO:K03099]
101284580  SOS2; son of sevenless homolog 2 isoform X2 [KO:K03099]
101271947  GTPase HRas-like isoform X4 [KO:K02833]
101286301  HRAS; GTPase HRas isoform X2 [KO:K02833]
101281897  KRAS; GTPase KRas isoform X2 [KO:K07827]
101276138  NRAS; GTPase NRas [KO:K07828]
101271966  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
101277195  BRAF; serine/threonine-protein kinase B-raf isoform X4 [KO:K04365] [EC:2.7.11.1]
101272984  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101286388  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101287162  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
101273287  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101289394  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101279541  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
101280971  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
101272639  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
101289479  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101289153  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
101284843  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101275711  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
101288096  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X3 [KO:K05696] [EC:3.1.3.48]
101289464  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X4 [KO:K05695] [EC:3.1.3.48]
101287701  MAPK9; mitogen-activated protein kinase 9 isoform X5 [KO:K04440] [EC:2.7.11.24]
101277656  MAPK10; mitogen-activated protein kinase 10 isoform X4 [KO:K04440] [EC:2.7.11.24]
101281228  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
101285763  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101269414  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
101278141  INPP5A; inositol polyphosphate-5-phosphatase A isoform X3 [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
oor00010  Glycolysis / Gluconeogenesis
oor00061  Fatty acid biosynthesis
oor00500  Starch and sucrose metabolism
oor04010  MAPK signaling pathway
oor04070  Phosphatidylinositol signaling system
oor04210  Apoptosis
KO pathway
ko04910   
LinkDB

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