KEGG   PATHWAY: cimi04910
Entry
cimi04910                   Pathway                                
Name
Insulin signaling pathway - Cebus imitator (Panamanian white-faced capuchin)
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
cimi04910  Insulin signaling pathway
cimi04910

Organism
Cebus imitator (Panamanian white-faced capuchin) [GN:cimi]
Gene
108288726  INS; insulin [KO:K04526]
108304133  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
108304802  IRS1; insulin receptor substrate 1 [KO:K16172]
108284872  IRS2; insulin receptor substrate 2 [KO:K07187]
108316556  IRS4; insulin receptor substrate 4 [KO:K17446]
108312772  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
108284538  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
108295514  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
108287732  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
108300786  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
108286022  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
108291018  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
108285792  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
108306856  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
108287186  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
108292532  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
108300247  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
108283908  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
108310362  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
108297310  LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269] [EC:3.1.3.16]
108313709  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
108315960  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
108308973  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
108309395  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
108282319  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
108315277  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
108285933  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
108293045  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
108293880  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
108294481  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
108296852  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
108298313  phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
108312632  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
108292098  CALM2; calmodulin-2 isoform X1 [KO:K02183]
108283821  CALM3; calmodulin-3 [KO:K02183]
108292329  CALML5; calmodulin-like protein 5 [KO:K02183]
108292331  CALML3; calmodulin-like protein 3 [KO:K02183]
108292617  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
108314009  CALML6; calmodulin-like protein 6 [KO:K02183]
108287993  PYGL; glycogen phosphorylase, liver form isoform X2 [KO:K00688] [EC:2.4.1.1]
108310281  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
108313136  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
108302166  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
108309036  LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
108284294  LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
108281936  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
108283458  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
108314512  PRKACG; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
108289006  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
108281667  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
108290370  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
108316804  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
108285729  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
108313954  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
108284994  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
108306596  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
108290593  FLOT1; flotillin-1 isoform X1 [KO:K07192]
108313661  FLOT2; flotillin-2 isoform X2 [KO:K07192]
108307945  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
108295714  SORBS1; sorbin and SH3 domain-containing protein 1 [KO:K06086]
108300640  CBL; E3 ubiquitin-protein ligase CBL isoform X2 [KO:K04707] [EC:2.3.2.27]
108305841  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
108313339  CRK; adapter molecule crk isoform X1 [KO:K04438]
108296215  CRKL; crk-like protein [KO:K04438]
108282973  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
108292088  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
108309452  exocyst complex component 7 [KO:K07195]
108304215  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
108293463  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
108312111  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
108313154  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
108301630  FASN; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
108297158  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
108318125  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
108318126  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
108289332  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
108292142  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
108293813  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
108314880  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
108307684  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
108290415  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
108293690  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
108297422  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
108309073  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
108316036  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
108313887  FOXO1; forkhead box protein O1 [KO:K07201]
108290096  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
108297042  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
108289795  G6PC1; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
108294299  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
108317038  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
108317039  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
108309953  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
108315364  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
108285700  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
108301563  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
108310354  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
108312078  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
108282470  40S ribosomal protein S6-like [KO:K02991]
108304333  40S ribosomal protein S6-like [KO:K02991]
108284011  RPS6; 40S ribosomal protein S6 [KO:K02991]
119472440  40S ribosomal protein S6-like [KO:K02991]
108309889  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
108292177  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
108294345  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
108294625  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
108295422  TSC1; hamartin [KO:K07206]
108290925  TSC2; tuberin isoform X1 [KO:K07207]
108297459  RHEB; GTP-binding protein Rheb [KO:K07208]
108310302  BAD; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
108292463  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
108297501  SHC2; SHC-transforming protein 2 [KO:K17447]
108304324  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
108315604  SHC4; SHC-transforming protein 4 [KO:K17449]
108309416  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
108287976  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
108293763  SOS1; son of sevenless homolog 1 [KO:K03099]
108288791  HRAS; GTPase HRas isoform X1 [KO:K02833]
108300272  KRAS; GTPase KRas isoform X2 [KO:K07827]
108289201  GTPase NRas-like [KO:K07828]
108301162  NRAS; GTPase NRas isoform X2 [KO:K07828]
108295532  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
108283419  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
108284634  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
108282680  dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:2.7.12.2]
108288453  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
108296669  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
108296197  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
108312786  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
108293175  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
108295535  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
108312172  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
108317927  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
108301748  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
108294062  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
108281329  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
108285145  tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
108313350  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
108315696  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
108286678  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
108295228  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
108316185  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
108307534  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
108292591  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
cimi00010  Glycolysis / Gluconeogenesis
cimi00061  Fatty acid biosynthesis
cimi00500  Starch and sucrose metabolism
cimi04010  MAPK signaling pathway
cimi04070  Phosphatidylinositol signaling system
cimi04210  Apoptosis
KO pathway
ko04910   
LinkDB

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