KEGG   PATHWAY: bom04910
Entry
bom04910                    Pathway                                
Name
Insulin signaling pathway - Bos mutus (wild yak)
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
bom04910  Insulin signaling pathway
bom04910

Organism
Bos mutus (wild yak) [GN:bom]
Gene
102264327  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102264463  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102265427  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102265515  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
102265814  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
102265930  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
102265959  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102266295  [KO:K02183]
102266436  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
102266815  LIPE; hormone-sensitive lipase isoform X2 [KO:K07188] [EC:3.1.1.79]
102266876  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102266922  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102266960  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102267219  [KO:K07208]
102267343  TSC2; tuberin isoform X1 [KO:K07207]
102268022  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
102268043  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
102268061  CALM2; calmodulin-2 isoform X2 [KO:K02183]
102268099  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
102268270  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
102268378  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
102268424  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
102268819  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
102268950  SHC3; SHC-transforming protein 3 [KO:K17448]
102269124  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102269203  NRAS; GTPase NRas [KO:K07828]
102269222  EXOC7; LOW QUALITY PROTEIN: exocyst complex component 7 [KO:K07195]
102269500  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
102269657  [KO:K02183]
102269695  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
102269809  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
102270280  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
102270322  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
102270414  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102270424  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
102270733  FLOT2; flotillin-2 isoform X1 [KO:K07192]
102270793  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
102270861  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
102271079  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
102271122  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
102271262  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X2 [KO:K07190]
102271339  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
102271710  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X2 [KO:K04369] [EC:2.7.12.2]
102271756  PCK1; LOW QUALITY PROTEIN: phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
102271961  [KO:K02183]
102272151  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
102272368  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102272421  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
102272556  SREBF1; LOW QUALITY PROTEIN: sterol regulatory element-binding protein 1 [KO:K07197]
102272943  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
102273017  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102273144  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
102273597  IRS4; insulin receptor substrate 4 [KO:K17446]
102273630  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
102274067  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
102274385  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
102274400  INS; insulin [KO:K04526]
102274461  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102274553  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102274606  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
102274810  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
102275095  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
102275206  ACACB; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102275213  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
102275260  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
102275376  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
102275377  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102275427  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
102275429  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102275581  PPP1R3E; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
102275975  BAD; bcl2-associated agonist of cell death [KO:K02158]
102276048  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X5 [KO:K07200]
102276125  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102277011  HRAS; GTPase HRas isoform X1 [KO:K02833]
102277025  CRKL; crk-like protein [KO:K04438]
102277134  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
102277548  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102277585  SOS2; son of sevenless homolog 2 [KO:K03099]
102277658  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
102277723  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
102277785  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
102277937  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
102277941  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
102277976  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102278222  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
102278235  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
102278267  FASN; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
102278368  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
102278478  FLOT1; flotillin-1 [KO:K07192]
102278591  [KO:K02833]
102278631  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
102278820  RPS6; small ribosomal subunit protein eS6 [KO:K02991]
102278844  CRK; adapter molecule crk isoform X1 [KO:K04438]
102278988  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
102279176  CBL; E3 ubiquitin-protein ligase CBL isoform X2 [KO:K04707] [EC:2.3.2.27]
102279229  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
102280296  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
102280361  [KO:K02183]
102280670  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
102280709  TSC1; hamartin isoform X1 [KO:K07206]
102281047  SHC2; SHC-transforming protein 2 [KO:K17447]
102281443  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102281667  CALM1; calmodulin-1 isoform X1 [KO:K02183]
102281727  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102281757  PRKACA; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102282476  CALM3; calmodulin-3 [KO:K02183]
102282841  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
102283212  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102284276  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102284406  CALML4; calmodulin-like protein 4 [KO:K02183]
102284488  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
102284499  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X2 [KO:K04372] [EC:2.7.11.1]
102284612  FOXO1; forkhead box protein O1 [KO:K07201]
102284664  IRS1; insulin receptor substrate 1 [KO:K16172]
102284710  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
102284931  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102285079  ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:2.7.11.1]
102285172  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
102285317  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
102285390  RPTOR; regulatory-associated protein of mTOR isoform X2 [KO:K07204]
102285484  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [KO:K01106] [EC:3.1.3.56]
102285710  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
102285847  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
102285968  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
102285991  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
102286114  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
102286241  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
102286409  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X11 [KO:K06277]
102286500  KRAS; GTPase KRas isoform X1 [KO:K07827]
102286868  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102286903  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
102286943  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102287221  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
102287375  [KO:K02183]
102288216  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102288249  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X1 [KO:K01084] [EC:3.1.3.9]
102288373  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
138985564  [KO:K17445]
138985600  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
138990232  IRS2; insulin receptor substrate 2 [KO:K07187]
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
bom00010  Glycolysis / Gluconeogenesis
bom00061  Fatty acid biosynthesis
bom00500  Starch and sucrose metabolism
bom04010  MAPK signaling pathway
bom04070  Phosphatidylinositol signaling system
bom04210  Apoptosis
KO pathway
ko04910   

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