KEGG   PATHWAY: eai04910
Entry
eai04910                    Pathway                                
Name
Insulin signaling pathway - Equus asinus (ass)
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
eai04910  Insulin signaling pathway
eai04910

Organism
Equus asinus (ass) [GN:eai]
Gene
106821924  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
106821933  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X2 [KO:K03259]
106822010  CRK; adapter molecule crk isoform X1 [KO:K04438]
106822593  [KO:K02649]
106822602  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X3 [KO:K04372] [EC:2.7.11.1]
106822865  [KO:K12407] [EC:2.7.1.2]
106823337  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
106823355  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
106824036  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
106824566  FLOT2; flotillin-2 isoform X1 [KO:K07192]
106824597  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X2 [KO:K07189]
106824750  PRKAA1; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
106824973  HRAS; GTPase HRas isoform X1 [KO:K02833]
106824993  PIK3R2; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
106825191  PRKAR2B; LOW QUALITY PROTEIN: cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
106825233  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
106825365  CALM1; calmodulin-1 [KO:K02183]
106825502  FLOT1; flotillin-1 isoform X1 [KO:K07192]
106825548  KRAS; GTPase KRas isoform X2 [KO:K07827]
106825573  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
106825676  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
106825844  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
106826000  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X6 [KO:K06276] [EC:2.7.11.1]
106826025  CALM2; calmodulin-2 [KO:K02183]
106826083  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
106826526  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X1 [KO:K01084] [EC:3.1.3.9]
106826959  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
106827396  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
106827854  IRS1; insulin receptor substrate 1 [KO:K16172]
106828491  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
106828516  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
106828693  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
106828957  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
106829188  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
106829211  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
106829313  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
106829345  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
106829397  [KO:K07827]
106829954  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
106830037  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
106830292  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
106830322  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
106830429  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
106830669  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
106830991  [KO:K04366] [EC:2.7.11.1]
106831177  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
106831384  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
106831625  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
106831860  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
106831907  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
106832322  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
106832731  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
106833475  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
106833496  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
106833503  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
106833616  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
106833626  BAD; bcl2-associated agonist of cell death [KO:K02158]
106833785  CALML5; calmodulin-like protein 5 [KO:K02183]
106833786  [KO:K02183]
106834045  RPS6; 40S ribosomal protein S6 [KO:K02991]
106834166  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
106834253  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
106834750  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
106835132  HK2; hexokinase-2 isoform X2 [KO:K00844] [EC:2.7.1.1]
106835326  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
106835360  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
106835457  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
106835498  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
106835678  NRAS; GTPase NRas [KO:K07828]
106836234  TSC2; tuberin [KO:K07207]
106836407  PPP1R3D; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3D [KO:K07189]
106836447  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
106836676  MTOR; serine/threonine-protein kinase mTOR isoform X3 [KO:K07203] [EC:2.7.11.1]
106836695  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
106836751  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
106836814  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
106837075  [KO:K06269] [EC:3.1.3.16]
106837686  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
106838100  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
106838201  IRS2; insulin receptor substrate 2 [KO:K07187]
106838266  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
106838460  PRKAG3; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
106838625  SHC4; SHC-transforming protein 4 [KO:K17449]
106838872  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
106839324  [KO:K17445]
106839337  SH2B2; LOW QUALITY PROTEIN: SH2B adapter protein 2 [KO:K07193]
106839421  MAPK10; mitogen-activated protein kinase 10 isoform X2 [KO:K04440] [EC:2.7.11.24]
106839496  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
106839506  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
106839597  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
106839711  IRS4; insulin receptor substrate 4 [KO:K17446]
106840141  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
106840308  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
106840596  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
106840602  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
106840645  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
106841072  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [KO:K01106] [EC:3.1.3.56]
106841112  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
106841113  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
106841135  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
106841479  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
106841633  SHC3; LOW QUALITY PROTEIN: SHC-transforming protein 3 [KO:K17448]
106842112  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X7 [KO:K06086]
106842216  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
106842618  BRAF; serine/threonine-protein kinase B-raf isoform X8 [KO:K04365] [EC:2.7.11.1]
106843289  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
106843713  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
106843729  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
106844181  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
106844316  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
106844524  INSR; insulin receptor isoform X2 [KO:K04527] [EC:2.7.10.1]
106844682  ACACA; acetyl-CoA carboxylase 1 isoform X4 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
106844778  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
106844842  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
106845014  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
106845016  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
106845168  CALM3; calmodulin-3 [KO:K02183]
106845190  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
106845213  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
106845267  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
106845368  TSC1; hamartin isoform X1 [KO:K07206]
106845379  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X4 [KO:K06277]
106845632  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
106845645  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
106846111  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
106846150  FASN; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
106846353  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
106847177  CALML4; calmodulin-like protein 4 isoform X2 [KO:K02183]
106847656  [KO:K07199]
106847914  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
106847941  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
106847984  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
106847985  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
106848074  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
106848262  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
106848274  CRKL; crk-like protein [KO:K04438]
106848479  FOXO1; forkhead box protein O1 [KO:K07201]
106848606  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
123280843  [KO:K07199]
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
eai00010  Glycolysis / Gluconeogenesis
eai00061  Fatty acid biosynthesis
eai00500  Starch and sucrose metabolism
eai04010  MAPK signaling pathway
eai04070  Phosphatidylinositol signaling system
eai04210  Apoptosis
KO pathway
ko04910   

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