KEGG   PATHWAY: mcf04910
Entry
mcf04910                    Pathway                                
Name
Insulin signaling pathway - Macaca fascicularis (crab-eating macaque)
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
mcf04910  Insulin signaling pathway
mcf04910

Organism
Macaca fascicularis (crab-eating macaque) [GN:mcf]
Gene
102133184  INS; insulin [KO:K04526]
102139081  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
102117978  IRS1; insulin receptor substrate 1 [KO:K16172]
102122241  IRS2; insulin receptor substrate 2 [KO:K07187]
102128819  IRS4; insulin receptor substrate 4 [KO:K17446]
102137291  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
101866246  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102124804  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102143464  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102142026  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102122725  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101866379  3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
102144461  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102142406  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102132744  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102133756  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
102145637  GYS2; glycogen [starch] synthase, liver isoform X2 [KO:K00693] [EC:2.4.1.11]
102134439  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
101925057  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102138402  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
102133300  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102116228  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
102116309  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
102146221  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
102123737  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
102127236  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102120225  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X2 [KO:K17453]
102125953  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
102128006  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
102118205  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
102133148  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
102138981  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
102119159  CALML6; calmodulin-like protein 6 [KO:K02183]
102114795  CALML3; calmodulin-like protein 3 [KO:K02183]
102146976  CALML5; calmodulin-like protein 5 [KO:K02183]
102131162  CALM1; calmodulin-1 [KO:K02183]
101866377  CALM3; calmodulin-3 [KO:K02183]
101865168  CALM2; calmodulin-2 [KO:K02183]
102122343  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
102144138  calmodulin-1 [KO:K02183]
102131984  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
102144832  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
102138647  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
102139399  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
102117414  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
102142443  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101926461  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X4 [KO:K04345] [EC:2.7.11.11]
101925248  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
102115738  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
102121067  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
107128539  LOW QUALITY PROTEIN: cAMP-dependent protein kinase type I-alpha regulatory subunit-like [KO:K04739]
102138641  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
102143368  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
101925905  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
102115718  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
102114914  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
101926288  FLOT1; flotillin-1 isoform X1 [KO:K07192]
102146856  FLOT2; flotillin-2 isoform X1 [KO:K07192]
102121730  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
102121582  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
102137660  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
102114949  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
102122623  CRKL; crk-like protein [KO:K04438]
101865065  CRK; adapter molecule crk isoform X1 [KO:K04438]
102137533  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
102122918  RHOQ; rho-related GTP-binding protein RhoQ isoform X4 [KO:K07194]
101865185  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
102140831  SREBF1; sterol regulatory element-binding protein 1 isoform X4 [KO:K07197]
102138812  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102116004  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102119674  FASN; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
102116429  PKLR; pyruvate kinase PKLR isoform X5 [KO:K12406] [EC:2.7.1.40]
102145864  HK1; hexokinase-1 isoform X3 [KO:K00844] [EC:2.7.1.1]
102147228  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
107126374  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
102121518  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
102127599  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
102143726  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
102144683  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101925338  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
102133927  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
102128414  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
102130217  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X3 [KO:K07200]
101865279  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
102116712  FOXO1; forkhead box protein O1 [KO:K07201]
102139030  LOW QUALITY PROTEIN: forkhead box protein O1-like [KO:K07201]
102125865  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X2 [KO:K07202]
102133548  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102144494  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
102139699  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102142152  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
102141498  FBP1; fructose-1,6-bisphosphatase 1 isoform X1 [KO:K03841] [EC:3.1.3.11]
102134909  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
102135856  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
102128371  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102116460  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
101925564  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X3 [KO:K04688] [EC:2.7.11.1]
102134845  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
101867274  RPS6; 40S ribosomal protein S6 [KO:K02991]
102129682  LOW QUALITY PROTEIN: 40S ribosomal protein S6 [KO:K02991]
123574044  40S ribosomal protein S6-like [KO:K02991]
102132583  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
102145554  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
101867078  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
102142223  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X3 [KO:K03259]
102124229  TSC1; hamartin isoform X1 [KO:K07206]
102140628  TSC2; tuberin isoform X1 [KO:K07207]
102127243  RHEB; GTP-binding protein Rheb [KO:K07208]
102121921  BAD; bcl2-associated agonist of cell death [KO:K02158]
102142777  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102125325  SHC2; SHC-transforming protein 2 [KO:K17447]
102130150  SHC3; SHC-transforming protein 3 [KO:K17448]
102130383  SHC4; SHC-transforming protein 4 [KO:K17449]
102118276  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
102135079  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102138313  SOS2; son of sevenless homolog 2 [KO:K03099]
102118744  HRAS; GTPase HRas isoform X1 [KO:K02833]
102131483  KRAS; GTPase KRas isoform X1 [KO:K07827]
102137913  NRAS; GTPase NRas [KO:K07828]
101925249  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
101866436  BRAF; serine/threonine-protein kinase B-raf isoform X4 [KO:K04365] [EC:2.7.11.1]
102125312  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102141214  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102140855  dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
102145011  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102116996  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
102129375  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X5 [KO:K04372] [EC:2.7.11.1]
102138091  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
102146168  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
102131144  ETS domain-containing protein Elk-1-like [KO:K04375]
102137357  ETS domain-containing protein Elk-1-like [KO:K04375]
102135411  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
102125352  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
102121569  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102141350  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
101865216  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
102129757  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X20 [KO:K05695] [EC:3.1.3.48]
102118497  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102126339  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102121272  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102146604  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
102115401  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
102124549  INPP5A; inositol polyphosphate-5-phosphatase A [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
mcf00010  Glycolysis / Gluconeogenesis
mcf00061  Fatty acid biosynthesis
mcf00500  Starch and sucrose metabolism
mcf04010  MAPK signaling pathway
mcf04070  Phosphatidylinositol signaling system
mcf04210  Apoptosis
KO pathway
ko04910   
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