KEGG   PATHWAY: uar04910
Entry
uar04910                    Pathway                                
Name
Insulin signaling pathway - Ursus americanus (American black bear)
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
uar04910  Insulin signaling pathway
uar04910

Organism
Ursus americanus (American black bear) [GN:uar]
Gene
123775502  INS; insulin [KO:K04526]
123775506  HRAS; GTPase HRas isoform X1 [KO:K02833]
123775611  TSC1; hamartin isoform X1 [KO:K07206]
123775730  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
123775818  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
123775918  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
123776226  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
123776524  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
123776714  IRS2; insulin receptor substrate 2 [KO:K07187]
123776869  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
123776898  CRK; adapter molecule crk isoform X1 [KO:K04438]
123776914  FLOT2; flotillin-2 isoform X1 [KO:K07192]
123777184  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
123777286  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
123777346  [KO:K17445]
123777569  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
123777917  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
123778092  IRS1; insulin receptor substrate 1 [KO:K16172]
123778279  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
123778404  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
123778440  BAD; bcl2-associated agonist of cell death [KO:K02158]
123778467  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
123778741  CALM3; calmodulin-3 [KO:K02183]
123778830  [KO:K02991]
123779002  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
123779078  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
123779112  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
123779126  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
123779467  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
123779650  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
123779728  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
123779926  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
123780083  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
123780203  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
123780295  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
123780399  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
123780404  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
123780411  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
123780802  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
123781308  RPS6; 40S ribosomal protein S6 [KO:K02991]
123781407  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
123781429  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
123781879  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
123782545  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
123782848  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
123782925  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
123783032  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
123783411  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
123783413  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
123783521  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
123783731  TSC2; tuberin isoform X1 [KO:K07207]
123783746  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
123783988  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
123784023  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
123784092  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
123784096  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
123784602  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
123784657  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
123784697  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
123785508  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
123785899  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
123785908  CALM2; calmodulin-2 [KO:K02183]
123785980  [KO:K02991]
123786093  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
123786380  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
123786407  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
123786515  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
123787940  ELK1; LOW QUALITY PROTEIN: ETS domain-containing protein Elk-1 [KO:K04375]
123788054  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
123788217  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
123788293  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
123788422  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
123788748  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
123788759  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
123788761  RHEB; GTP-binding protein Rheb [KO:K07208]
123788872  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
123789043  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
123789398  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
123789458  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
123790062  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
123790496  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
123790763  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
123791373  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
123791665  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
123791741  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
123791891  FOXO1; LOW QUALITY PROTEIN: forkhead box protein O1 [KO:K07201]
123792161  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
123792654  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
123793149  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
123793291  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
123793473  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
123793519  [KO:K02991]
123793733  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
123793748  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
123793798  PTPRF; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
123793926  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
123794000  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
123794070  [KO:K17447]
123794277  FLOT1; flotillin-1 isoform X1 [KO:K07192]
123794785  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
123795037  NRAS; GTPase NRas [KO:K07828]
123795174  [KO:K06269] [EC:3.1.3.16]
123795272  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
123795384  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
123795639  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
123795650  CRKL; crk-like protein [KO:K04438]
123795763  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
123795782  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
123796079  CALML6; calmodulin-like protein 6 [KO:K02183]
123796122  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
123796391  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
123796818  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
123797188  PPP1R3F; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3F [KO:K17453]
123798898  CALM1; calmodulin-1 [KO:K02183]
123799360  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
123799809  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
123799882  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
123800028  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [KO:K01106] [EC:3.1.3.56]
123800228  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
123800287  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
123800359  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
123800746  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
123800842  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
123800861  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
123800940  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
123801660  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
123801699  KRAS; GTPase KRas isoform X1 [KO:K07827]
123801768  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
123801854  SHC4; SHC-transforming protein 4 [KO:K17449]
123802053  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
123802291  [KO:K02183]
123802321  CALML3; calmodulin-like protein 3 [KO:K02183]
123802510  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
123802720  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
123802898  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X1 [KO:K04739]
123802938  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
123802954  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
123803038  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
123803186  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
123803229  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
123803330  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
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
uar00010  Glycolysis / Gluconeogenesis
uar00061  Fatty acid biosynthesis
uar00500  Starch and sucrose metabolism
uar04010  MAPK signaling pathway
uar04070  Phosphatidylinositol signaling system
uar04210  Apoptosis
KO pathway
ko04910   

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