KEGG   PATHWAY: biu04910
Entry
biu04910                    Pathway                                
Name
Insulin signaling pathway - Bos indicus (zebu cattle)
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
biu04910  Insulin signaling pathway
biu04910

Organism
Bos indicus (zebu cattle) [GN:biu]
Gene
109554336  INS; insulin isoform X1 [KO:K04526]
109571355  IRS1; insulin receptor substrate 1 [KO:K16172]
109567100  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
109578427  insulin receptor substrate 1-like [KO:K17445]
109555543  IRS4; insulin receptor substrate 4 [KO:K17446]
109574805  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
109561418  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109556345  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109559805  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109570415  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
109557823  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
109578066  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
109572496  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109570286  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109571966  glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
109572216  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
109559597  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
109554414  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
109571193  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
109566263  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
109567662  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
109553499  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
109564802  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
109557421  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
109553067  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
109555262  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
109578248  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
109578294  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
109571646  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
109555458  phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
109565417  CALM1; calmodulin [KO:K02183]
109575003  calmodulin-alpha-like [KO:K02183]
109566056  CALM2; calmodulin [KO:K02183]
109568081  calmodulin-like [KO:K02183]
109570679  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
109572535  CALM3; calmodulin isoform X1 [KO:K02183]
109564712  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
109567623  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
109554068  glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
109554069  glycogen phosphorylase, muscle form-like [KO:K00688] [EC:2.4.1.1]
109565026  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
109569608  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
109556827  PRKACB; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
109561498  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
109573375  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
109557384  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
109575887  cAMP-dependent protein kinase type II-alpha regulatory subunit-like [KO:K04739]
109576064  cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
109572731  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
109570580  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
109558232  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
109574066  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
109574080  FLOT2; flotillin-2 isoform X1 [KO:K07192]
109577072  FLOT1; flotillin-1 [KO:K07192]
109578305  SH2B2; SH2B adapter protein 2 [KO:K07193]
109579053  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
109568806  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
109568926  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
109570977  CRKL; crk-like protein [KO:K04438]
109573847  CRK; adapter molecule crk isoform X1 [KO:K04438]
109566561  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
109566049  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
109574102  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
109561683  TRIP10; cdc42-interacting protein 4 [KO:K07196]
109573629  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
109573799  acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109571092  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109573330  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
109553613  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
109553833  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
109565473  hexokinase-2-like [KO:K00844] [EC:2.7.1.1]
109561886  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
109565895  hexokinase-2 [KO:K00844] [EC:2.7.1.1]
109553626  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
109557544  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
109574812  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
109556244  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
109574695  5'-AMP-activated protein kinase catalytic subunit alpha-1-like [KO:K07198] [EC:2.7.11.31]
109555847  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
109571380  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
109570727  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
109557811  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
109559147  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
109566997  FOXO1; forkhead box protein O1 [KO:K07201]
109560366  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
109573874  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
109576447  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
109574284  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
109563232  FBP2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
109563233  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
109564787  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
109567303  PCK1; LOW QUALITY PROTEIN: phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
109570401  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109573755  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
109554358  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
109573726  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
109571278  40S ribosomal protein S6 [KO:K02991]
109562461  RPS6; 40S ribosomal protein S6 [KO:K02991]
109553533  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
109572117  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
109560989  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
109560323  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
109566571  TSC1; hamartin isoform X1 [KO:K07206]
109578279  TSC2; tuberin isoform X1 [KO:K07207]
109557810  RHEB; GTP-binding protein Rheb [KO:K07208]
109554386  BAD; bcl2-associated agonist of cell death [KO:K02158]
109553931  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
109561056  SHC2; SHC-transforming protein 2 [KO:K17447]
109562580  SHC3; SHC-transforming protein 3 [KO:K17448]
109565147  SHC4; SHC-transforming protein 4 [KO:K17449]
109574040  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
109566002  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
109564346  SOS2; son of sevenless homolog 2 [KO:K03099]
109560940  GTPase HRas-like [KO:K02833]
109559581  KRAS; GTPase KRas isoform X1 [KO:K07827]
109555890  NRAS; GTPase NRas [KO:K07828]
109555027  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
109557698  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
109576053  RAF1; LOW QUALITY PROTEIN: RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
109564697  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109561751  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
109578667  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
109570973  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
109561807  MKNK2; LOW QUALITY PROTEIN: MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
109556334  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
109555031  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
109578851  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
109558981  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
109574319  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
109565183  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
109567547  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
109556400  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
109561331  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
109560650  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
109553773  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109553353  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
109569627  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
109579046  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [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
biu00010  Glycolysis / Gluconeogenesis
biu00061  Fatty acid biosynthesis
biu00500  Starch and sucrose metabolism
biu04010  MAPK signaling pathway
biu04070  Phosphatidylinositol signaling system
biu04210  Apoptosis
KO pathway
ko04910   
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