KEGG   PATHWAY: bmus04910
Entry
bmus04910                   Pathway                                
Name
Insulin signaling pathway - Balaenoptera musculus (blue 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
bmus04910  Insulin signaling pathway
bmus04910

Organism
Balaenoptera musculus (blue whale) [GN:bmus]
Gene
118899337  INS; insulin [KO:K04526]
118892062  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
118897871  IRS1; insulin receptor substrate 1 [KO:K16172]
118883967  IRS2; insulin receptor substrate 2 [KO:K07187]
118881371  insulin receptor substrate 1-like [KO:K17445]
118888242  IRS4; insulin receptor substrate 4 [KO:K17446]
118891709  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118892996  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
118901944  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
118892181  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118894592  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
118894671  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118880851  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
118884787  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118900614  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118890216  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118894954  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
118884924  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
118901850  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
118898761  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
118905689  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
118879939  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
118890937  PPP1R3E; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
118881176  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
118887980  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
118901082  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
118883082  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
118889037  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
118880673  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
118880833  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
118884712  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
118888414  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
118888530  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
118884881  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
118885208  CALM3; calmodulin-3 [KO:K02183]
118905963  CALM2; calmodulin-2 [KO:K02183]
118886337  calmodulin-alpha-like [KO:K02183]
118889669  CALM1; calmodulin-1 [KO:K02183]
118889785  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
118883503  calmodulin-1-like [KO:K02183]
118890671  CALML5; calmodulin-like protein 5 [KO:K02183]
118891255  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
118899466  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
118880638  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
118899002  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
118892306  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
118903730  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
118880521  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
118887551  PRKAR1A; LOW QUALITY PROTEIN: cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
118901029  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
118903373  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
118885038  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
118901701  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
118894743  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
118886981  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
118886728  FLOT2; flotillin-2 isoform X1 [KO:K07192]
118903639  FLOT1; flotillin-1 [KO:K07192]
118881351  SH2B2; SH2B adapter protein 2 [KO:K07193]
118882754  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
118899117  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
118894212  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
118886751  CRK; adapter molecule crk isoform X1 [KO:K04438]
118906942  CRKL; crk-like protein [KO:K04438]
118896559  RAPGEF1; LOW QUALITY PROTEIN: rap guanine nucleotide exchange factor 1 [KO:K06277]
118905713  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
118887088  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
118892847  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
118887057  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
118886187  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118906860  acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118886381  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
118884027  PKLR; LOW QUALITY PROTEIN: pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
118906046  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
118882499  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
118883066  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
118901272  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
118893106  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
118890034  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
118898524  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
118906832  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
118898407  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
118900839  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
118902461  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
118884195  FOXO1; forkhead box protein O1 [KO:K07201]
118895621  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
118898470  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
118886111  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
118887159  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
118894052  LOW QUALITY PROTEIN: glucose-6-phosphatase 3-like [KO:K01084] [EC:3.1.3.9]
118896768  FBP1; fructose-1,6-bisphosphatase 1 isoform X1 [KO:K03841] [EC:3.1.3.11]
118897362  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
118881863  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
118890676  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
118889583  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
118886692  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
118898758  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
118886231  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
118897490  RPS6; 40S ribosomal protein S6 [KO:K02991]
118898298  40S ribosomal protein S6-like [KO:K02991]
118905637  40S ribosomal protein S6-like [KO:K02991]
118899799  40S ribosomal protein S6-like [KO:K02991]
118896837  40S ribosomal protein S6-like [KO:K02991]
118887997  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
118904013  eukaryotic translation initiation factor 4E-like [KO:K03259]
118884835  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
118898050  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
118892557  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
118895494  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
118889712  eukaryotic translation initiation factor 4E [KO:K03259]
118896887  TSC1; hamartin isoform X1 [KO:K07206]
118880802  TSC2; tuberin isoform X1 [KO:K07207]
118900608  RHEB; GTP-binding protein Rheb [KO:K07208]
118899830  BAD; bcl2-associated agonist of cell death [KO:K02158]
118893636  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118893410  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
118896483  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
118890587  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
118886410  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
118906231  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
118889611  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118892044  GTPase HRas-like [KO:K02833]
118899209  HRAS; GTPase HRas isoform X1 [KO:K02833]
118901791  KRAS; GTPase KRas isoform X1 [KO:K07827]
118893681  NRAS; GTPase NRas [KO:K07828]
118888277  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
118900685  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
118904127  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118891063  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
118892655  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
118880663  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
118906690  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
118891850  MKNK2; LOW QUALITY PROTEIN: MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
118896615  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
118889133  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
118881276  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
118902022  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
118887332  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
118890695  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
118880814  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
118891345  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
118893249  MAPK9; LOW QUALITY PROTEIN: mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
118896118  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118883114  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118887797  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
118899386  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
118882765  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [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
bmus00010  Glycolysis / Gluconeogenesis
bmus00061  Fatty acid biosynthesis
bmus00500  Starch and sucrose metabolism
bmus04010  MAPK signaling pathway
bmus04070  Phosphatidylinositol signaling system
bmus04210  Apoptosis
KO pathway
ko04910   
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