KEGG   PATHWAY: vlg04910
Entry
vlg04910                    Pathway                                
Name
Insulin signaling pathway - Vulpes lagopus (Arctic fox)
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
vlg04910  Insulin signaling pathway
vlg04910

Organism
Vulpes lagopus (Arctic fox) [GN:vlg]
Gene
121471415  INS; insulin [KO:K04526]
121494318  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
121496830  IRS1; insulin receptor substrate 1 [KO:K16172]
121476873  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
121483169  IRS4; insulin receptor substrate 4 [KO:K17446]
121481416  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
121496480  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
121494738  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
121477352  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
121478805  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
121499678  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
121488142  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
121488903  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
121482033  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
121482375  LOW QUALITY PROTEIN: RAC-gamma serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
121493415  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
121489623  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
121484228  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
121480162  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
121475295  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
121472051  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
121491037  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
121489582  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
121474747  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
121485538  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
121478300  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
121493846  PPP1R3E; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
121483383  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
121487929  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
121487998  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
121482842  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
121482970  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
121497363  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
121485632  CALML4; calmodulin-like protein 4 [KO:K02183]
121485676  CALM3; calmodulin-3 [KO:K02183]
121485677  calmodulin-1 [KO:K02183]
121478795  calmodulin-1 [KO:K02183]
121496486  calmodulin-like protein 3 [KO:K02183]
121497964  CALML5; calmodulin-like protein 5 [KO:K02183]
121490986  CALM2; calmodulin-2 [KO:K02183]
121493011  CALM1; calmodulin-1 [KO:K02183]
121500599  CALML6; calmodulin-like protein 6 [KO:K02183]
121493375  calmodulin-alpha-like [KO:K02183]
121478910  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
121492918  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
121501818  PYGM; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
121476440  PDE3B; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
121486651  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
121495416  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
121488362  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
121473421  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
121494764  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
121501746  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
121484344  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
121499817  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
121477501  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
121500373  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
121473429  FLOT2; flotillin-2 isoform X1 [KO:K07192]
121489915  FLOT1; flotillin-1 isoform X1 [KO:K07192]
121486265  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
121485435  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
121499521  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
121488606  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
121473371  CRK; adapter molecule crk isoform X1 [KO:K04438]
121475542  CRKL; crk-like protein [KO:K04438]
121473724  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
121492211  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
121473649  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
121495522  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
121499758  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
121472547  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
121475814  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
121472961  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
121488418  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
121486269  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
121486645  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
121486953  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
121491114  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
121489105  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
121486591  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
121499646  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
121475788  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
121491188  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
121480576  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
121490132  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
121480059  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
121496787  FOXO1; forkhead box protein O1 [KO:K07201]
121490101  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
121473770  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
121472640  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
121501492  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
121484494  FBP1; fructose-1,6-bisphosphatase 1 isoform X1 [KO:K03841] [EC:3.1.3.11]
121484789  FBP2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
121478309  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
121493122  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
121496713  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
121472564  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
121471453  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
121472885  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
121481987  40S ribosomal protein S6-like [KO:K02991]
121482324  40S ribosomal protein S6 [KO:K02991]
121494537  RPS6; 40S ribosomal protein S6 isoform X1 [KO:K02991]
121489233  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
121480324  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
121483203  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
121485288  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-like [KO:K03259]
121487719  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
121497303  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
121493470  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
121473130  TSC1; hamartin [KO:K07206]
121487228  TSC2; tuberin isoform X1 [KO:K07207]
121489596  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
121501608  BAD; bcl2-associated agonist of cell death [KO:K02158]
121485053  SHC1; SHC-transforming protein 1 [KO:K06279]
121494261  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
121485154  SHC3; SHC-transforming protein 3 [KO:K17448]
121485135  SHC4; SHC-transforming protein 4 [KO:K17449]
121473934  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
121491936  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
121493142  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
121472124  HRAS; GTPase HRas isoform X1 [KO:K02833]
121479900  KRAS; GTPase KRas isoform X1 [KO:K07827]
121491321  NRAS; GTPase NRas [KO:K07828]
121483180  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
121489076  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
121494281  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
121484067  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
121495470  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
121475510  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
121486545  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
121481543  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
121495603  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
121483151  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
121487606  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
121481595  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
121474160  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
121493618  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
121478162  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
121481123  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
121482830  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
121493739  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
121494640  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
121489510  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
121476369  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
121484412  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
vlg00010  Glycolysis / Gluconeogenesis
vlg00061  Fatty acid biosynthesis
vlg00500  Starch and sucrose metabolism
vlg04010  MAPK signaling pathway
vlg04070  Phosphatidylinositol signaling system
vlg04210  Apoptosis
KO pathway
ko04910   
LinkDB

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