KEGG   PATHWAY: sbq04910
Entry
sbq04910                    Pathway                                
Name
Insulin signaling pathway - Saimiri boliviensis boliviensis (Bolivian squirrel 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
sbq04910  Insulin signaling pathway
sbq04910

Organism
Saimiri boliviensis boliviensis (Bolivian squirrel monkey) [GN:sbq]
Gene
101038116  INS; insulin [KO:K04526]
101028986  INSR; insulin receptor isoform X3 [KO:K04527] [EC:2.7.10.1]
101035868  IRS1; insulin receptor substrate 1 [KO:K16172]
101038649  IRS2; insulin receptor substrate 2 [KO:K07187]
101035392  IRS4; insulin receptor substrate 4 [KO:K17446]
101032496  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101033359  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101050592  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101029768  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101052779  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101027982  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101032521  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101034861  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101045714  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101040766  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101051107  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
101040983  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
101050509  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
101030626  serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
101050671  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
101048497  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
101048398  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
101042521  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
101028256  PPP1R3E; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3E [KO:K07189]
101027923  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
101046723  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
101044739  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
101035738  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
101045885  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
101048522  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
101039573  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X2 [KO:K07190]
101052401  PHKB; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
101054139  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X2 [KO:K07190]
101036413  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
101031785  calmodulin-alpha-like [KO:K02183]
101041174  CALML6; calmodulin-like protein 6 isoform X2 [KO:K02183]
101029957  CALM3; calmodulin [KO:K02183]
101047982  CALM2; calmodulin [KO:K02183]
101039332  CALML3; calmodulin-like protein 3 [KO:K02183]
101039863  CALML5; calmodulin-like protein 5 [KO:K02183]
101049022  CALM1; LOW QUALITY PROTEIN: calmodulin [KO:K02183]
101044400  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
101032178  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
101053900  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
101046670  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
101034152  cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
101036705  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101043989  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma isoform X1 [KO:K04345] [EC:2.7.11.11]
101047300  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101046297  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
101031797  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
101033992  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
101046367  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
101041035  LOW QUALITY PROTEIN: cAMP-dependent protein kinase type II-alpha regulatory subunit-like [KO:K04739]
101052652  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
101039978  PRKCZ; protein kinase C zeta type isoform X4 [KO:K18952] [EC:2.7.11.13]
101037993  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
101032629  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
101053543  FLOT2; flotillin-2 isoform X1 [KO:K07192]
101034411  FLOT1; flotillin-1 isoform X1 [KO:K07192]
101032970  SH2B adapter protein 2-like [KO:K07193]
101038807  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
101053489  CBL; LOW QUALITY PROTEIN: E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
101035841  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
101051048  CRKL; crk-like protein [KO:K04438]
101029260  CRK; adapter molecule crk [KO:K04438]
101052399  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
101050639  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
101035165  EXOC7; exocyst complex component 7 [KO:K07195]
101053269  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
101029259  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
101031989  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101037726  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101045175  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
101040510  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
101047051  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
101049162  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
101047634  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
101029285  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
101027980  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
101030830  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X2 [KO:K07198] [EC:2.7.11.31]
101033212  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101029046  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101051388  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
101028682  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
101044457  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
101042380  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
101053657  FOXO1; forkhead box protein O1 [KO:K07201]
101046514  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X2 [KO:K07202]
101036723  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
101033884  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
101032250  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
101028234  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
101028557  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
101027719  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
101035593  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X2 [KO:K01596] [EC:4.1.1.32]
101047083  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101039601  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
101033758  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
101038541  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101038852  RPS6; 40S ribosomal protein S6 [KO:K02991]
101030055  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-binding protein 1-like [KO:K07205]
101029508  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101043550  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
101031713  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101048462  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101028002  TSC1; hamartin isoform X1 [KO:K07206]
101031475  TSC2; tuberin isoform X5 [KO:K07207]
101049631  BAD; bcl2-associated agonist of cell death [KO:K02158]
101038895  SHC1; SHC-transforming protein 1 [KO:K06279]
101047748  SHC-transforming protein 1 [KO:K06279]
101048523  SHC2; SHC-transforming protein 2 [KO:K17447]
101028764  SHC3; SHC-transforming protein 3 [KO:K17448]
101032627  SHC4; SHC-transforming protein 4 [KO:K17449]
101038666  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101036943  SOS1; son of sevenless homolog 1 [KO:K03099]
101046427  SOS2; son of sevenless homolog 2 [KO:K03099]
101047663  HRAS; GTPase HRas isoform X2 [KO:K02833]
101047035  KRAS; GTPase KRas isoform X1 [KO:K07827]
101036877  NRAS; GTPase NRas [KO:K07828]
101043605  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101052142  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
101054052  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
101040361  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101036151  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101038546  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101043202  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101053960  MKNK2; LOW QUALITY PROTEIN: MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
101044769  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X2 [KO:K04372] [EC:2.7.11.1]
101045005  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
101050866  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101040467  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
101046533  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101034850  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
101045896  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
101042719  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
101039160  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101027742  MAPK9; mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
101048066  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101052971  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
101029956  INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
101037105  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [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
sbq00010  Glycolysis / Gluconeogenesis
sbq00061  Fatty acid biosynthesis
sbq00500  Starch and sucrose metabolism
sbq04010  MAPK signaling pathway
sbq04070  Phosphatidylinositol signaling system
sbq04210  Apoptosis
KO pathway
ko04910   
LinkDB

DBGET integrated database retrieval system