KEGG   PATHWAY: rro04910
Entry
rro04910                    Pathway                                
Name
Insulin signaling pathway - Rhinopithecus roxellana (golden snub-nosed monkey)
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
rro04910  Insulin signaling pathway
rro04910

Organism
Rhinopithecus roxellana (golden snub-nosed monkey) [GN:rro]
Gene
104677102  INS; insulin [KO:K04526]
104679498  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
104656078  IRS1; insulin receptor substrate 1 [KO:K16172]
104679253  IRS2; insulin receptor substrate 2 [KO:K07187]
104676250  IRS4; insulin receptor substrate 4 [KO:K17446]
104662124  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
104675620  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
104680672  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
104663050  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
104665061  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
104670605  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
104661825  LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
104682713  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
104673041  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104676121  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
104654186  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
115893905  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
104680990  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
104660892  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
104666538  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
104675136  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
104664823  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
104668466  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
104663883  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
104674153  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
104671183  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
104654320  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
104680996  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
104661819  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X2 [KO:K17453]
104661547  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
104675874  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
104655440  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
104662717  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
104668823  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
104662055  calmodulin [KO:K02183]
104663170  CALM2; calmodulin-2 [KO:K02183]
104680741  calmodulin-alpha-like [KO:K02183]
104670544  CALM1; calmodulin-1 [KO:K02183]
104673406  CALM3; calmodulin-3 [KO:K02183]
104664834  CALML5; calmodulin-like protein 5 [KO:K02183]
104664835  CALML3; calmodulin-like protein 3 [KO:K02183]
104653554  CALML6; calmodulin-like protein 6 isoform X2 [KO:K02183]
104662590  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
104674211  calmodulin-alpha-like [KO:K02183]
104656871  calmodulin-like [KO:K02183]
104661021  PYGB; glycogen phosphorylase, brain form isoform X2 [KO:K00688] [EC:2.4.1.1]
104662855  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
104682740  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
104681940  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
104662061  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma isoform X1 [KO:K04345] [EC:2.7.11.11]
104677489  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
104661051  LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
104667688  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
104677403  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
104664935  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
104654031  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X2 [KO:K04739]
104658678  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
104653559  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
104671216  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
104673327  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
104674112  FLOT2; flotillin-2 isoform X1 [KO:K07192]
104666200  FLOT1; flotillin-1 isoform X1 [KO:K07192]
104681196  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
104664673  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
104657236  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
104674409  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
104666852  CRKL; crk-like protein [KO:K04438]
104670311  CRK; adapter molecule crk isoform X1 [KO:K04438]
104669757  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
104663189  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
104681278  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
104665358  TRIP10; cdc42-interacting protein 4 isoform X2 [KO:K07196]
104665664  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
104672993  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
104660172  ACACB; acetyl-CoA carboxylase 2 isoform X2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
104654984  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
104659593  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
104661961  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
104661963  HK1; hexokinase-1 isoform X2 [KO:K00844] [EC:2.7.1.1]
104680441  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
104674833  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
104671144  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
104676941  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
104664292  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
104678672  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
104666241  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
104660035  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X2 [KO:K07200]
104679727  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
104678710  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X3 [KO:K07200]
104671116  FOXO1; forkhead box protein O1 isoform X2 [KO:K07201]
104662089  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
104679987  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
104655034  G6PC2; LOW QUALITY PROTEIN: glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
104654704  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
104669112  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
104669113  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
104662705  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X2 [KO:K01596] [EC:4.1.1.32]
104663782  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
104654362  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
104654941  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
104662932  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
104664740  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
104664248  RPS6; 40S ribosomal protein S6 [KO:K02991]
104668286  40S ribosomal protein S6-like [KO:K02991]
115892949  40S ribosomal protein S6 [KO:K02991]
104679650  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
104664097  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
104680439  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
104655162  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
104669743  TSC1; hamartin isoform X2 [KO:K07206]
104681538  TSC2; tuberin isoform X1 [KO:K07207]
104678707  RHEB; GTP-binding protein Rheb [KO:K07208]
104673141  BAD; bcl2-associated agonist of cell death [KO:K02158]
104663483  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
104668515  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
104657941  SHC4; SHC-transforming protein 4 [KO:K17449]
104681311  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
104663024  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
104682751  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
104654600  HRAS; GTPase HRas isoform X1 [KO:K02833]
104670041  KRAS; GTPase KRas isoform X1 [KO:K07827]
104669078  NRAS; GTPase NRas [KO:K07828]
104664593  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
104659700  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
104673299  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
104662575  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
104665487  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
104676897  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
104681150  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
104662110  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
104671399  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X3 [KO:K04372] [EC:2.7.11.1]
104664595  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
104667710  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
104678596  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
104677022  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
104669147  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
104678520  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
104669035  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
104676194  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
104678447  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
104668007  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
104666046  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
104665152  INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
104677635  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [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
rro00010  Glycolysis / Gluconeogenesis
rro00061  Fatty acid biosynthesis
rro00500  Starch and sucrose metabolism
rro04010  MAPK signaling pathway
rro04070  Phosphatidylinositol signaling system
rro04210  Apoptosis
KO pathway
ko04910   
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