KEGG   PATHWAY: vvp04910
Entry
vvp04910                    Pathway                                
Name
Insulin signaling pathway - Vulpes vulpes (red 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
vvp04910  Insulin signaling pathway
vvp04910

Organism
Vulpes vulpes (red fox) [GN:vvp]
Gene
112924140  INS; insulin [KO:K04526]
112909702  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
112925532  IRS1; insulin receptor substrate 1 [KO:K16172]
112927496  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
112932035  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
112914774  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
112913170  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
112935820  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
112924665  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
112926217  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
112934961  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
112909152  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
112928376  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112930303  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
112923528  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
112913469  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
112917536  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
112931234  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
112933024  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
112924187  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
112935190  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
112926511  PPP1R3E; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
112916093  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
112929857  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
112913797  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
112932212  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
112907212  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
112929247  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
112934117  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
112907641  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
112919129  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
112931643  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
112927180  calmodulin-alpha-like [KO:K02183]
112926172  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
112915227  CALM2; calmodulin-2 [KO:K02183]
112930936  CALML4; calmodulin-like protein 4 [KO:K02183]
112931188  CALM3; calmodulin-3 [KO:K02183]
112907343  CALM1; calmodulin-1 [KO:K02183]
112907557  CALML5; calmodulin-like protein 5 [KO:K02183]
112933710  CALML3; calmodulin-like protein 3 [KO:K02183]
112924300  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
112933248  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
112921440  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
112926998  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
112908063  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
112924478  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
112911908  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
112908555  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
112920740  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
112929283  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
112931218  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
112926173  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
112926694  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
112924825  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
112913572  FLOT1; flotillin-1 [KO:K07192]
112933049  FLOT2; flotillin-2 isoform X1 [KO:K07192]
112935733  SH2B2; SH2B adapter protein 2 [KO:K07193]
112914048  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
112920322  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
112913407  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
112907448  CRKL; crk-like protein [KO:K04438]
112933059  CRK; adapter molecule crk isoform X1 [KO:K04438]
112927996  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
112915221  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
112920820  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
112911828  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
112924964  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
112917969  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
112910485  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
112920917  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
112918921  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
112916701  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
112923912  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
112923920  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
112925741  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
112911707  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
112933502  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
112926098  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
112907666  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
112932888  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
112916245  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
112922478  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
112921100  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
112918703  FOXO1; forkhead box protein O1 [KO:K07201]
112918943  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
112910664  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
112916524  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
112910824  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
112908705  FBP1; fructose-1,6-bisphosphatase 1 isoform X1 [KO:K03841] [EC:3.1.3.11]
112908710  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
112926529  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
112932263  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
112929738  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
112920880  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
112917940  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
112924182  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
112925882  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
112922008  RPS6; 40S ribosomal protein S6 [KO:K02991]
112916127  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
112927950  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
112928517  eukaryotic translation initiation factor 4E type 2-like isoform X1 [KO:K03259]
112916519  eukaryotic translation initiation factor 4E type 2 [KO:K03259]
112925497  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
112932657  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
112928006  TSC1; hamartin isoform X1 [KO:K07206]
112909041  TSC2; tuberin isoform X1 [KO:K07207]
112916202  RHEB; GTP-binding protein Rheb [KO:K07208]
112924315  BAD; bcl2-associated agonist of cell death [KO:K02158]
112918897  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
112935467  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
112908627  SHC3; SHC-transforming protein 3 [KO:K17448]
112920045  SHC4; SHC-transforming protein 4 [KO:K17449]
112920790  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
112921310  SOS2; son of sevenless homolog 2 [KO:K03099]
112935267  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
112914428  HRAS; GTPase HRas isoform X1 [KO:K02833]
112917213  KRAS; GTPase KRas isoform X1 [KO:K07827]
112916766  NRAS; GTPase NRas [KO:K07828]
112907269  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
112907060  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
112933694  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
112935545  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
112929340  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
112907501  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
112914758  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
112935499  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
112907276  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
112923240  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
112914913  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
112920856  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
112921409  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
112931859  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
112914825  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
112913098  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
112911881  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
112919676  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
112916156  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
112928740  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
112928852  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
vvp00010  Glycolysis / Gluconeogenesis
vvp00061  Fatty acid biosynthesis
vvp00500  Starch and sucrose metabolism
vvp04010  MAPK signaling pathway
vvp04070  Phosphatidylinositol signaling system
vvp04210  Apoptosis
KO pathway
ko04910   
LinkDB

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