KEGG   PATHWAY: hmh04910
Entry
hmh04910                    Pathway                                
Name
Insulin signaling pathway - Hylobates moloch (silvery gibbon)
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
hmh04910  Insulin signaling pathway
hmh04910

Organism
Hylobates moloch (silvery gibbon) [GN:hmh]
Gene
116456249  SOCS4; suppressor of cytokine signaling 4 isoform X1 [KO:K04697]
116456560  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
116456569  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
116456631  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
116456977  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
116457620  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
116457903  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
116458112  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
116458283  CRK; adapter molecule crk isoform X1 [KO:K04438]
116458418  PRKACG; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
116458837  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
116458853  HK1; hexokinase-1 isoform X2 [KO:K00844] [EC:2.7.1.1]
116458915  CRKL; crk-like protein [KO:K04438]
116459111  RPS6; small ribosomal subunit protein eS6 [KO:K02991]
116459126  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
116459323  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
116460087  FLOT1; flotillin-1 [KO:K07192]
116460769  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
116461134  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
116461260  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
116461451  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
116461632  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
116461671  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
116461687  [KO:K03259]
116461880  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
116462105  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116462317  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
116462653  TSC2; tuberin isoform X1 [KO:K07207]
116462749  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
116462998  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
116463128  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
116463291  [KO:K07189]
116463380  [KO:K07189]
116464064  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
116464630  [KO:K17447]
116465188  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
116466571  HRAS; GTPase HRas isoform X3 [KO:K02833]
116466754  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
116466871  [KO:K02183]
116466895  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
116466926  [KO:K03259]
116466990  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X2 [KO:K22517] [EC:2.3.2.27]
116467191  FOXO1; forkhead box protein O1 [KO:K07201]
116467516  [KO:K02183]
116467557  IRS2; insulin receptor substrate 2 [KO:K07187]
116468021  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
116468949  BAD; bcl2-associated agonist of cell death [KO:K02158]
116468964  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
116469076  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
116469079  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
116469318  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
116469345  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
116469568  NRAS; GTPase NRas [KO:K07828]
116469844  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
116470222  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
116470224  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
116470570  [KO:K00871] [EC:2.7.11.19]
116471214  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
116471905  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
116471910  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
116471970  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
116472430  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
116472766  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
116472788  KRAS; GTPase KRas isoform X1 [KO:K07827]
116473036  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X5 [KO:K05695] [EC:3.1.3.48]
116473104  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
116473498  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
116473835  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
116474153  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
116474442  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
116474552  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
116474591  FLOT2; flotillin-2 isoform X1 [KO:K07192]
116474613  CALML5; calmodulin-like protein 5 [KO:K02183]
116474621  CALML3; calmodulin-like protein 3 [KO:K02183]
116474929  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
116475219  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
116475274  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
116475275  FBP1; fructose-1,6-bisphosphatase 1 isoform X1 [KO:K03841] [EC:3.1.3.11]
116475789  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
116475805  TSC1; hamartin isoform X1 [KO:K07206]
116476485  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
116476641  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
116477056  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
116477841  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
116477930  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
116477970  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
116478223  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
116478297  INPP5A; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
116478308  CALM3; calmodulin-3 [KO:K02183]
116478341  TRIP10; cdc42-interacting protein 4 isoform X2 [KO:K07196]
116478549  [KO:K02991]
116478588  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
116478691  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
116479100  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
116479486  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
116480512  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
116480602  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
116480683  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
116481235  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
116481263  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116481523  SHC4; SHC-transforming protein 4 [KO:K17449]
116482295  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
116482339  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
116482952  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
116483000  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
116483146  CALM2; calmodulin-2 isoform X1 [KO:K02183]
116483190  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
116483233  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
116483411  SREBF1; sterol regulatory element-binding protein 1 isoform X2 [KO:K07197]
116483548  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116483604  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
116483953  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
116484009  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
116484019  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
116484062  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
116484153  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
116484470  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
116484846  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
116484917  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
116484949  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
116485139  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
116485193  CALM1; calmodulin-1 isoform X2 [KO:K02183]
116809650  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
116810071  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
116810145  IRS1; insulin receptor substrate 1 [KO:K16172]
116810283  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
116810414  [KO:K00665] [EC:2.3.1.85]
116810699  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
116810979  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
116811101  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
116811640  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
116811691  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
116811948  IRS4; insulin receptor substrate 4 [KO:K17446]
116812280  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
116812491  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
116812799  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
116812889  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116812918  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
116813883  CALML6; calmodulin-like protein 6 [KO:K02183]
116814225  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
116814342  [KO:K04369] [EC:2.7.12.2]
116814428  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
116814554  RHEB; GTP-binding protein Rheb [KO:K07208]
116814555  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
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
hmh00010  Glycolysis / Gluconeogenesis
hmh00061  Fatty acid biosynthesis
hmh00500  Starch and sucrose metabolism
hmh04010  MAPK signaling pathway
hmh04070  Phosphatidylinositol signaling system
hmh04210  Apoptosis
KO pathway
ko04910   

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