KEGG   PATHWAY: umr04910
Entry
umr04910                    Pathway                                
Name
Insulin signaling pathway - Ursus maritimus (polar 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
umr04910  Insulin signaling pathway
umr04910

Organism
Ursus maritimus (polar bear) [GN:umr]
Gene
103657110  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
103657204  CALM3; calmodulin-3 [KO:K02183]
103657827  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
103657874  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
103658371  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
103658509  INPP5A; inositol polyphosphate-5-phosphatase A isoform X2 [KO:K01106] [EC:3.1.3.56]
103658535  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
103659011  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
103659098  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
103659121  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
103659532  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
103660099  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
103660467  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
103660589  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
103660943  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
103660987  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
103661038  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103661277  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
103662156  RPS6; 40S ribosomal protein S6 [KO:K02991]
103662312  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
103662640  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
103662668  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
103662712  IRS1; insulin receptor substrate 1 [KO:K16172]
103662753  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
103662972  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
103663057  [KO:K03259]
103663185  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
103663617  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
103664348  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
103664456  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
103664677  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
103664763  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
103665005  FLOT1; flotillin-1 isoform X1 [KO:K07192]
103665227  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
103665244  KRAS; GTPase KRas isoform X1 [KO:K07827]
103665409  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
103665582  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
103665677  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
103665736  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
103665758  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
103665967  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
103665983  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
103666012  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
103666660  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
103666688  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103666874  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
103666919  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
103667312  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
103667329  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
103667406  FLOT2; flotillin-2 isoform X1 [KO:K07192]
103667783  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
103667893  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
103667955  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
103668004  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
103668258  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
103668383  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
103668498  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
103668697  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
103668779  TSC2; tuberin isoform X1 [KO:K07207]
103668888  [KO:K02991]
103669103  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
103669173  [KO:K02833]
103669230  CRKL; crk-like protein [KO:K04438]
103669286  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103669422  NRAS; GTPase NRas [KO:K07828]
103669540  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
103669667  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
103669924  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
103670034  [KO:K17445]
103670188  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
103670203  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
103670250  TSC1; hamartin [KO:K07206]
103670304  CALM1; calmodulin-1 isoform X1 [KO:K02183]
103670406  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
103670673  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
103670750  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X2 [KO:K04372] [EC:2.7.11.1]
103670766  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
103670905  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
103670947  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
103670991  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
103671035  HRAS; GTPase HRas isoform X3 [KO:K02833]
103671240  CALM2; calmodulin-2 [KO:K02183]
103671429  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
103671764  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
103671891  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
103671909  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
103672592  G6PC1; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
103673077  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
103673813  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
103674684  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
103674708  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
103675105  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
103675162  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
103675232  [KO:K02991]
103675453  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
103676125  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103676211  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
103676238  [KO:K02183]
103676239  CALML3; calmodulin-like protein 3 [KO:K02183]
103676308  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
103676722  SHC4; SHC-transforming protein 4 [KO:K17449]
103676878  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
103676947  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
103677059  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
103677350  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
103677704  FOXO1; forkhead box protein O1 [KO:K07201]
103677918  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
103678107  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
103678278  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
103678332  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X2 [KO:K07199]
103678344  ACACB; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
103678391  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
103678447  PRKCZ; protein kinase C zeta type isoform X2 [KO:K18952] [EC:2.7.11.13]
103678592  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
103678785  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
103679049  CALML4; calmodulin-like protein 4 isoform X3 [KO:K02183]
103679064  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103679274  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X2 [KO:K01596] [EC:4.1.1.32]
103679423  BAD; bcl2-associated agonist of cell death [KO:K02158]
103679516  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
103679558  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
103679611  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
103679770  IRS4; insulin receptor substrate 4 [KO:K17446]
103679990  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
103680155  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
103680194  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
103681043  [KO:K07189]
103681753  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
103681796  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
103681834  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
103681873  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
103681916  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
103682041  CALML6; calmodulin-like protein 6 [KO:K02183]
103682183  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103682210  FBP2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
103682232  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
103682384  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
121099752  [KO:K07189]
121099769  INS; insulin [KO:K04526]
121100270  [KO:K07189]
121101028  [KO:K02991]
121101279  IRS2; insulin receptor substrate 2 [KO:K07187]
121103675  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
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
umr00010  Glycolysis / Gluconeogenesis
umr00061  Fatty acid biosynthesis
umr00500  Starch and sucrose metabolism
umr04010  MAPK signaling pathway
umr04070  Phosphatidylinositol signaling system
umr04210  Apoptosis
KO pathway
ko04910   

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