KEGG   PATHWAY: pret04910
Entry
pret04910                   Pathway                                
Name
Insulin signaling pathway - Poecilia reticulata (guppy)
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
pret04910  Insulin signaling pathway
pret04910

Organism
Poecilia reticulata (guppy) [GN:pret]
Gene
103470901  insulin-like [KO:K04526]
103476384  insulin isoform X2 [KO:K04526]
103479883  insr; LOW QUALITY PROTEIN: insulin receptor [KO:K04527] [EC:2.7.10.1]
103480483  insulin receptor substrate 1-B-like [KO:K16172]
103459734  irs2; insulin receptor substrate 2 [KO:K07187]
103476518  insulin receptor substrate 2-like isoform X1 [KO:K07187]
103474601  insulin receptor substrate 2-B-like [KO:K07187]
103480255  insulin receptor substrate 2-B-like [KO:K07187]
103463201  pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
103463319  phosphatidylinositol 3-kinase regulatory subunit gamma-like isoform X1 [KO:K02649]
103470780  phosphatidylinositol 3-kinase regulatory subunit alpha-like isoform X1 [KO:K02649]
103473324  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
103478998  phosphatidylinositol 3-kinase regulatory subunit gamma-like isoform X1 [KO:K02649]
103479173  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
103463230  pik3ca; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103467210  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
103475907  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
103474947  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
103479066  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103481066  pdpk1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
103458546  akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
103470003  RAC-gamma serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
103474789  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
103476681  RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
103459583  gsk3b; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
103459579  gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
103469092  gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
103458750  ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
103469528  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
103468963  serine/threonine-protein phosphatase alpha-2 isoform-like [KO:K06269] [EC:3.1.3.16]
103480185  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
103481373  serine/threonine-protein phosphatase alpha-2 isoform-like [KO:K06269] [EC:3.1.3.16]
103465616  protein phosphatase 1 regulatory subunit 3D-like isoform X1 [KO:K07189]
103459471  ppp1r3a; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
103462879  protein phosphatase 1 regulatory subunit 3E-like [KO:K07189]
103465926  uncharacterized protein LOC103465926 [KO:K07189]
103467246  protein phosphatase 1 regulatory subunit 3D-like isoform X1 [KO:K07189]
103470537  protein phosphatase 1 regulatory subunit 3C-like [KO:K07189]
103473984  protein phosphatase 1 regulatory subunit 3B-like [KO:K07189]
103474051  ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
103477182  ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
103474557  phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
103481060  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
103462037  phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
103462219  phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
103480412  phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
103457807  calm1; calmodulin [KO:K02183]
103458787  calmodulin [KO:K02183]
103474632  calm3; calmodulin [KO:K02183]
103477335  calm2; calmodulin [KO:K02183]
103458479  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
103475454  glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
103480109  glycogen phosphorylase, muscle form-like [KO:K00688] [EC:2.4.1.1]
103462442  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
103464159  prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
103468785  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
103479663  cAMP-dependent protein kinase catalytic subunit beta-like isoform X1 [KO:K04345] [EC:2.7.11.11]
103481100  prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103466327  prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
103467117  prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
103469193  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
103481956  prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
103473021  hormone-sensitive lipase-like isoform X1 [KO:K07188] [EC:3.1.1.79]
103477914  lipe; hormone-sensitive lipase isoform X6 [KO:K07188] [EC:3.1.1.79]
103466966  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
103479885  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
103480459  slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
103472976  flotillin-1-like [KO:K07192]
103475233  flotillin-2-like [KO:K07192]
103476048  flot2; flotillin-2 isoform X1 [KO:K07192]
103477962  flot1; flotillin-1 [KO:K07192]
103474674  sh2b2; SH2B adapter protein 2 [KO:K07193]
103477189  sorbin and SH3 domain-containing protein 1 [KO:K06086]
103476312  E3 ubiquitin-protein ligase CBL-like [KO:K04707] [EC:2.3.2.27]
103474573  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
103473580  crkl; crk-like protein [KO:K04438]
103474879  crk; adapter molecule crk isoform X1 [KO:K04438]
103476349  adapter molecule crk-like [KO:K04438]
103473427  rap guanine nucleotide exchange factor 1-like isoform X1 [KO:K06277]
103477342  rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
103481594  exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
103462107  cdc42-interacting protein 4 homolog [KO:K07196]
103468878  cdc42-interacting protein 4 homolog [KO:K07196]
103469249  srebf1; sterol regulatory element-binding protein 1 [KO:K07197]
103475899  acaca; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
103470346  acacb; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
103482177  fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
103462842  hexokinase-1-like [KO:K00844] [EC:2.7.1.1]
103462844  putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
103462845  hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
103470212  hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
103469787  hexokinase-2-like [KO:K00844] [EC:2.7.1.1]
103470005  gck; glucokinase [KO:K12407] [EC:2.7.1.2]
103473399  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
103463785  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
103469702  5'-AMP-activated protein kinase subunit beta-1-like [KO:K07199]
103479357  5'-AMP-activated protein kinase subunit beta-2-like [KO:K07199]
103465268  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
103460160  5'-AMP-activated protein kinase subunit gamma-2-like isoform X1 [KO:K07200]
103475605  5'-AMP-activated protein kinase subunit gamma-1-like isoform X1 [KO:K07200]
103479581  5'-AMP-activated protein kinase subunit gamma-1-like isoform X1 [KO:K07200]
103482256  5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
103475797  foxo1; forkhead box protein O1 [KO:K07201]
103475003  forkhead box protein O1-A-like [KO:K07201]
103480692  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
103461716  g6pc2; glucose-6-phosphatase 2 isoform X2 [KO:K01084] [EC:3.1.3.9]
103481660  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
103481693  g6pc; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
103481694  glucose-6-phosphatase-like [KO:K01084] [EC:3.1.3.9]
103470739  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
103470743  fructose-1,6-bisphosphatase isozyme 2-like [KO:K03841] [EC:3.1.3.11]
103473350  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
103464655  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
103482322  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
103467091  mtor; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
103463551  rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
103474395  ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
103472417  ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
103476099  ribosomal protein S6 kinase beta-1-like [KO:K04688] [EC:2.7.11.1]
103466016  rps6; 40S ribosomal protein S6 [KO:K02991]
103473570  eukaryotic translation initiation factor 4E-binding protein 3-like [KO:K07205]
103470286  eukaryotic translation initiation factor 4E-binding protein 1-like [KO:K07205]
103460523  eukaryotic translation initiation factor 4E-1A-like isoform X1 [KO:K03259]
103471822  eukaryotic translation initiation factor 4E-1A [KO:K03259]
103476881  eukaryotic translation initiation factor 4E-like isoform X1 [KO:K03259]
103479370  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X2 [KO:K03259]
103473966  tsc1; hamartin [KO:K07206]
103465672  tsc2; tuberin isoform X1 [KO:K07207]
103460145  rheb; GTP-binding protein Rheb [KO:K07208]
103465263  rhebl1; GTPase RhebL1 [KO:K07208]
103479739  GTP-binding protein Rheb [KO:K07208]
103480747  bad; bcl2-associated agonist of cell death [KO:K02158]
103478162  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
103463557  shc2; SHC-transforming protein 2 [KO:K17447]
103473860  SHC-transforming protein 3 [KO:K17448]
103462081  shc4; SHC-transforming protein 4 [KO:K17449]
103468398  grb2; growth factor receptor-bound protein 2 [KO:K04364]
103461060  son of sevenless homolog 2-like [KO:K03099]
103471606  sos1; son of sevenless homolog 1 [KO:K03099]
103458478  sos2; son of sevenless homolog 2 [KO:K03099]
103466143  hras; GTPase HRas [KO:K02833]
103466102  kras; GTPase KRas isoform X1 [KO:K07827]
103469088  GTPase HRas-like [KO:K07827]
103469576  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
103459555  braf; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
103467582  raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
103466546  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103463649  map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
103470721  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103469111  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103463590  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
103468229  mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
103460239  elk1; ETS domain-containing protein Elk-1 [KO:K04375]
103462961  suppressor of cytokine signaling 1-like [KO:K04694]
103468587  socs1; suppressor of cytokine signaling 1 [KO:K04694]
103459817  suppressor of cytokine signaling 2 [KO:K04695]
103461355  suppressor of cytokine signaling 3-like [KO:K04696]
103481519  socs3; suppressor of cytokine signaling 3 [KO:K04696]
103462934  suppressor of cytokine signaling 4 [KO:K04697]
103467754  tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
103479767  ptprf; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
103464223  receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
103473893  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
103471253  mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
103476945  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
103482024  mapk8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
103470025  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
103471620  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2B-like [KO:K15909] [EC:3.1.3.86]
103474471  inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
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
pret00010  Glycolysis / Gluconeogenesis
pret00061  Fatty acid biosynthesis
pret00500  Starch and sucrose metabolism
pret04010  MAPK signaling pathway
pret04070  Phosphatidylinositol signaling system
pret04210  Apoptosis
KO pathway
ko04910   
LinkDB

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