KEGG   PATHWAY: uah04910
Entry
uah04910                    Pathway                                
Name
Insulin signaling pathway - Ursus arctos (brown 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
uah04910  Insulin signaling pathway
uah04910

Organism
Ursus arctos (brown bear) [GN:uah]
Gene
113240761  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
113240885  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
113240902  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
113241090  [KO:K02183]
113241128  [KO:K02183]
113241174  IRS4; insulin receptor substrate 4 [KO:K17446]
113241493  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
113241494  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X7 [KO:K07200]
113241630  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
113242251  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
113242351  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
113242690  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
113242755  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
113242822  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
113242888  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
113242935  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
113243106  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
113243320  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
113243394  CALM3; calmodulin-3 [KO:K02183]
113243430  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
113243521  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
113243572  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
113243960  INS; insulin [KO:K04526]
113244028  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
113244033  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
113244160  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
113244178  BAD; bcl2-associated agonist of cell death [KO:K02158]
113244394  NRAS; GTPase NRas isoform X2 [KO:K07828]
113244480  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
113244532  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
113244564  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
113244605  EXOC7; exocyst complex component 7 isoform X2 [KO:K07195]
113244637  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
113245065  [KO:K02991]
113245080  TSC2; LOW QUALITY PROTEIN: tuberin [KO:K07207]
113245274  PKLR; pyruvate kinase PKLR isoform X2 [KO:K12406] [EC:2.7.1.40]
113245295  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
113245405  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X2 [KO:K06276] [EC:2.7.11.1]
113245546  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
113245604  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
113245972  CALM2; calmodulin-2 [KO:K02183]
113246063  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
113246083  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
113246097  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
113246251  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
113247020  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
113247057  CRKL; crk-like protein [KO:K04438]
113247197  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
113247514  [KO:K02991]
113247754  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
113249088  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
113250342  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X2 [KO:K03259]
113250390  IRS1; insulin receptor substrate 1 [KO:K16172]
113250445  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
113250824  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X3 [KO:K22517] [EC:2.3.2.27]
113251282  FOXO1; forkhead box protein O1 [KO:K07201]
113251536  IRS2; insulin receptor substrate 2 [KO:K07187]
113251754  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X35 [KO:K06086]
113251972  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
113252083  INPP5A; inositol polyphosphate-5-phosphatase A isoform X3 [KO:K01106] [EC:3.1.3.56]
113252209  PHKB; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
113253989  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113254486  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
113254619  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
113254716  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X4 [KO:K04372] [EC:2.7.11.1]
113254730  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
113254783  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X3 [KO:K05695] [EC:3.1.3.48]
113254799  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
113255228  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
113255266  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
113256068  [KO:K02183]
113256161  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
113256705  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
113256848  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
113257190  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
113257659  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
113257792  KRAS; GTPase KRas isoform X1 [KO:K07827]
113257808  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
113257909  GCK; LOW QUALITY PROTEIN: hexokinase-4 [KO:K12407] [EC:2.7.1.2]
113258614  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
113258718  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X2 [KO:K05696] [EC:3.1.3.48]
113258758  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
113258780  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
113259127  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
113259128  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
113259962  CBL; E3 ubiquitin-protein ligase CBL isoform X2 [KO:K04707] [EC:2.3.2.27]
113260592  RPS6; 40S ribosomal protein S6 [KO:K02991]
113260929  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
113261548  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
113262099  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
113262116  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
113262966  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113263092  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
113263123  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
113263180  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
113263893  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
113264133  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
113264353  FLOT1; flotillin-1 isoform X2 [KO:K07192]
113265167  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
113265236  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X2 [KO:K04739]
113265366  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
113265393  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
113265953  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
113265980  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
113265986  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
113266205  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
113266218  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
113266537  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X7 [KO:K06277]
113266547  TSC1; hamartin isoform X1 [KO:K07206]
113266747  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X4 [KO:K07202]
113266966  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
113267029  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
113267083  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
113267192  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113267365  CALM1; calmodulin-1 isoform X2 [KO:K02183]
113267539  [KO:K02991]
113267646  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
113267697  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
113267739  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
113267828  SH2B2; SH2B adapter protein 2 isoform X2 [KO:K07193]
113267858  [KO:K17445]
113268897  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
113268927  ACACA; acetyl-CoA carboxylase 1 isoform X4 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
113269051  FLOT2; flotillin-2 isoform X3 [KO:K07192]
113269112  CRK; adapter molecule crk isoform X1 [KO:K04438]
113269258  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
113269597  SHC4; SHC-transforming protein 4 [KO:K17449]
113269785  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
113269786  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
113270120  SHC3; SHC-transforming protein 3 [KO:K17448]
113270510  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
113270537  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113270615  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
113270682  CALML6; calmodulin-like protein 6 [KO:K02183]
113270798  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
113271115  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
113271299  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
125282300  HRAS; GTPase HRas isoform X1 [KO:K02833]
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
uah00010  Glycolysis / Gluconeogenesis
uah00061  Fatty acid biosynthesis
uah00500  Starch and sucrose metabolism
uah04010  MAPK signaling pathway
uah04070  Phosphatidylinositol signaling system
uah04210  Apoptosis
KO pathway
ko04910   

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