KEGG   PATHWAY: xtr04910
Entry
xtr04910                    Pathway                                
Name
Insulin signaling pathway - Xenopus tropicalis (tropical clawed frog)
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
xtr04910  Insulin signaling pathway
xtr04910

Organism
Xenopus tropicalis (tropical clawed frog) [GN:xtr]
Gene
100101718  ins; insulin precursor [KO:K04526]
100492718  insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
100495320  irs1; insulin receptor substrate 1 isoform X1 [KO:K16172]
394823  irs2; insulin receptor substrate 1 [KO:K16172]
100196925  irs4; insulin receptor substrate 4 [KO:K07187]
100498409  insulin receptor substrate 2 [KO:K07187]
549983  pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100486835  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100497001  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
780390  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100144924  pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
779524  pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
100144709  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100490038  akt1; RAC-alpha serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100489648  gsk3b; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100490155  gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
407879  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
496958  ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100145598  ppp1ca; protein phosphatase 1, catalytic subunit, alpha isozyme [KO:K06269] [EC:3.1.3.16]
548704  ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
100127791  ppp1r3c.1; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100036661  ppp1r3a; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
100490113  ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
448158  ppp1r3c.2; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100486852  ppp1r3e; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100486900  protein phosphatase 1 regulatory subunit 3D [KO:K07189]
448255  phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
779740  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
100158624  phka1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
100493974  phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
100498261  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X2 [KO:K07190]
493522  calm1; calmodulin [KO:K02183]
100496298  calm2; calmodulin-2 [KO:K02183]
496530  calml4; calmodulin-like protein 4 [KO:K02183]
431680  pygm; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
779523  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100491051  glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100487373  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
549157  prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100038053  prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
116407821  putative protein kinase C delta type homolog [KO:K04345] [EC:2.7.11.11]
116407822  putative protein kinase C delta type homolog [KO:K04345] [EC:2.7.11.11]
116407825  protein kinase C delta type-like [KO:K04345] [EC:2.7.11.11]
108648814  protein kinase C delta type [KO:K04345] [EC:2.7.11.11]
100488597  protein kinase C delta type [KO:K04345] [EC:2.7.11.11]
105946713  protein kinase C delta type [KO:K04345] [EC:2.7.11.11]
101731553  serine/threonine-protein kinase N1 [KO:K04345] [EC:2.7.11.11]
116411737  protein kinase C delta type-like [KO:K04345] [EC:2.7.11.11]
780384  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
594933  prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
100486265  prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
100495356  prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
733899  lipe; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
100101769  prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
503517  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
101731550  slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
496443  flot2; flotillin-2 [KO:K07192]
733927  flot1; flotillin-1 [KO:K07192]
100490322  flotillin-2 [KO:K07192]
100488327  sh2b2; SH2B adapter protein 2 isoform X1 [KO:K07193]
100380148  sorbs1; sorbin and SH3 domain-containing protein 1 isoform X7 [KO:K06086]
594900  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
448509  cblb; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
448023  crk; adapter molecule crk [KO:K04438]
394657  crkl; crk-like protein [KO:K04438]
733953  rapgef1; rap guanine nucleotide exchange factor 1 [KO:K06277]
100497782  rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
549650  exoc7; exocyst complex component 7 [KO:K07195]
100485631  srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
100495654  acaca; acetyl-CoA carboxylase 1 isoform X4 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100192373  acacb; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100487052  fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
100380137  pklr; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
100124752  hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
100145699  hk2; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100485269  hkdc1; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
100493823  hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
100492955  hexokinase-2 [KO:K00844] [EC:2.7.1.1]
100124905  gck; glucokinase [KO:K12407] [EC:2.7.1.2]
100145520  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
100216099  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
100127782  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
100380160  prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
779860  prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100158499  prkag2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
100125135  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
493378  foxo1; forkhead box protein O1 [KO:K07201]
100491667  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
448183  g6pc.3; glucose-6-phosphatase, catalytic subunit, gene 3 [KO:K01084] [EC:3.1.3.9]
100125173  g6pc.1; glucose-6-phosphatase, catalytic subunit, gene 1 [KO:K01084] [EC:3.1.3.9]
100127753  g6pc.2; glucose-6-phosphatase, catalytic subunit, gene 2 [KO:K01084] [EC:3.1.3.9]
779477  g6pc3.1; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
394750  fbp1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
613108  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
116406685  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
116406747  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
100485303  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
394790  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
733907  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100491970  mtor; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100170605  rptor; regulatory-associated protein of mTOR [KO:K07204]
394938  rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
394757  rps6; 40S ribosomal protein S6 [KO:K02991]
448677  eif4e2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
548663  eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
548830  eif4e2; eukaryotic translation initiation factor 4E family member 2 [KO:K03259]
100127761  eif4e1b; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
100380126  tsc1; hamartin isoform X1 [KO:K07206]
100170546  tsc2; tuberin [KO:K07207]
548676  rheb; GTP-binding protein Rheb [KO:K07208]
100487418  bad; bcl2-associated agonist of cell death [KO:K02158]
116406911  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
100487416  shc2; SHC-transforming protein 2 [KO:K17447]
100101768  shc3; SHC-transforming protein 3 [KO:K17448]
100490718  shc4; SHC-transforming protein 4 [KO:K17449]
493492  grb2; growth factor receptor-bound protein 2 [KO:K04364]
100489960  sos1; son of sevenless homolog 1 [KO:K03099]
100497015  sos2; son of sevenless homolog 2 [KO:K03099]
549757  hras; GTPase HRas [KO:K02833]
493396  kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
100485959  krasl; GTPase KRas isoform X2 [KO:K07827]
549517  nras; GTPase NRas [KO:K07828]
100495479  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
779570  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
549871  raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
493420  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
549881  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
493413  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
780232  mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
100497609  elk1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
496789  socs1; suppressor of cytokine signaling 1 [KO:K04694]
108647342  suppressor of cytokine signaling 1 [KO:K04694]
100151723  socs2; suppressor of cytokine signaling 2 [KO:K04695]
448204  socs3; suppressor of cytokine signaling 3 [KO:K04696]
394588  socs3l; suppressor of cytokine signaling 3-Like [KO:K04696]
549828  socs4; suppressor of cytokine signaling 4 [KO:K04697]
549875  ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
100493254  ptprf; receptor-type tyrosine-protein phosphatase F isoform X8 [KO:K05695] [EC:3.1.3.48]
779515  mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
100170194  mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
448125  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100485745  inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
100496685  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like [KO:K15909] [EC:3.1.3.86]
548959  inpp5a.1; 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
xtr00010  Glycolysis / Gluconeogenesis
xtr00061  Fatty acid biosynthesis
xtr00500  Starch and sucrose metabolism
xtr04010  MAPK signaling pathway
xtr04070  Phosphatidylinositol signaling system
xtr04210  Apoptosis
KO pathway
ko04910   
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