KEGG   PATHWAY: loc04910
Entry
loc04910                    Pathway                                
Name
Insulin signaling pathway - Lepisosteus oculatus (spotted gar)
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
loc04910  Insulin signaling pathway
loc04910

Organism
Lepisosteus oculatus (spotted gar) [GN:loc]
Gene
102694874  insulin-like [KO:K04526]
102695073  insulin-like isoform X2 [KO:K04526]
102696537  insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
102684310  insulin receptor substrate 2-A-like [KO:K16172]
102696987  irs1; insulin receptor substrate 1 [KO:K16172]
102682802  irs2; insulin receptor substrate 2 [KO:K07187]
102693755  irs4; insulin receptor substrate 4 isoform X3 [KO:K07187]
102693436  pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X3 [KO:K02649]
102696821  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
102687995  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
102691786  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
102685070  pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102688673  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102695429  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102691100  pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102690433  akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102684446  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102691207  akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102692161  gsk3b; glycogen synthase kinase-3 beta isoform X4 [KO:K03083] [EC:2.7.11.26]
102686347  gys2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
102683699  ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102699172  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102696354  serine/threonine-protein phosphatase PP1(5.9)-like [KO:K06269] [EC:3.1.3.16]
102685218  protein phosphatase 1 regulatory subunit 3E-like [KO:K07189]
102687268  ppp1r3b; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
102689970  protein phosphatase 1 regulatory subunit 3C-B-like isoform X1 [KO:K07189]
107079452  ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K07189]
102690152  ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102684645  ppp1r3c; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
102685810  ppp1r3a; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
102695754  phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
102693577  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
102698483  phka1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
102698788  phkb; phosphorylase b kinase regulatory subunit beta isoform X3 [KO:K07190]
102688560  calm3; calmodulin [KO:K02183]
102688815  calm2; calmodulin [KO:K02183]
102690259  calml4; calmodulin-like protein 4 [KO:K02183]
102695922  calm1; calmodulin [KO:K02183]
102691846  calml6; calmodulin-like protein 6 [KO:K02183]
102685557  pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
102697297  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
102693395  pygm; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
102694452  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
102688918  prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102686951  prkaca; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
102687087  prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
102698232  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
102684925  prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
102694948  prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
102689231  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
102688875  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
102682554  slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
102694252  flot2; flotillin-2 isoform X1 [KO:K07192]
102687796  sh2b2; SH2B adapter protein 2 isoform X1 [KO:K07193]
102698616  sorbs1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
102693589  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
102691528  cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
102683891  adapter molecule crk-like [KO:K04438]
102695616  crkl; crk-like protein [KO:K04438]
102697581  rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
102694376  rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
102693158  exoc7; exocyst complex component 7 isoform X11 [KO:K07195]
102683726  trip10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
102693907  srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
102686789  acaca; acetyl-CoA carboxylase 1 isoform X2 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102687665  acacb; acetyl-CoA carboxylase 2 isoform X7 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102685951  fasn; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
102698058  hexokinase-2 [KO:K00844] [EC:2.7.1.1]
102687490  hk3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
102695978  hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
102687955  putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
102694132  gck; glucokinase isoform X2 [KO:K12407] [EC:2.7.1.2]
102693561  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X2 [KO:K07198] [EC:2.7.11.31]
102698529  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
102688739  prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
102687363  5'-AMP-activated protein kinase subunit beta-2-like isoform X1 [KO:K07199]
102683132  prkag3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X2 [KO:K07200]
102683649  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
102684542  prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
102685236  foxo1; forkhead box protein O1 [KO:K07201]
102687278  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X4 [KO:K07202]
102689892  glucose-6-phosphatase-like isoform X1 [KO:K01084] [EC:3.1.3.9]
102691948  g6pc2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102690091  g6pc; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
102692158  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
102682959  LOW QUALITY PROTEIN: fructose-1,6-bisphosphatase isozyme 2-like [KO:K03841] [EC:3.1.3.11]
102683163  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
102694774  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
102692856  mtor; serine/threonine-protein kinase mTOR isoform X2 [KO:K07203] [EC:2.7.11.1]
102682722  rptor; regulatory-associated protein of mTOR [KO:K07204]
102695696  rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
102691816  ribosomal protein S6 kinase beta-2-like [KO:K04688] [EC:2.7.11.1]
102686669  rps6; 40S ribosomal protein S6 [KO:K02991]
102689159  eukaryotic translation initiation factor 4E-binding protein 1-like [KO:K07205]
102685148  eif4e2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
102685112  eif4e; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
102697157  eukaryotic translation initiation factor 4E-like isoform X4 [KO:K03259]
102696571  eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
102697582  hamartin-like isoform X1 [KO:K07206]
102698706  tsc2; tuberin isoform X1 [KO:K07207]
102693805  rhebl1; GTPase RhebL1 [KO:K07208]
102685538  rheb; GTP-binding protein Rheb isoform X2 [KO:K07208]
102684095  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102690296  SHC-transforming protein 2-like isoform X1 [KO:K17447]
102685302  shc3; SHC-transforming protein 3 isoform X1 [KO:K17448]
102684593  shc4; SHC-transforming protein 4 isoform X1 [KO:K17449]
102696581  grb2; growth factor receptor-bound protein 2 [KO:K04364]
102692301  sos1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102696513  sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
102697398  hras; GTPase HRas [KO:K02833]
102696189  kras; GTPase KRas isoform X3 [KO:K07827]
102691327  nras; GTPase NRas [KO:K07828]
102687735  LOW QUALITY PROTEIN: serine/threonine-protein kinase A-Raf-like [KO:K08845] [EC:2.7.11.1]
102693824  braf; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
102692545  raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102691532  map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
102686784  map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
102683764  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102682518  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
102686902  mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X2 [KO:K04372] [EC:2.7.11.1]
102693793  elk1; ETS domain-containing protein Elk-1 [KO:K04375]
102693371  socs1; suppressor of cytokine signaling 1 [KO:K04694]
102698069  cish; cytokine-inducible SH2-containing protein [KO:K04695]
102692411  socs2; suppressor of cytokine signaling 2 [KO:K04695]
102690014  socs3; suppressor of cytokine signaling 3 [KO:K04696]
102683522  socs4; suppressor of cytokine signaling 4 [KO:K04697]
102693115  ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
102684943  ptprf; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
102687878  mapk10; mitogen-activated protein kinase 10 isoform X4 [KO:K04440] [EC:2.7.11.24]
102692400  mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102691138  mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
102690045  ikbkb; LOW QUALITY PROTEIN: inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102690663  inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
102682643  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2B-like isoform X1 [KO:K15909] [EC:3.1.3.86]
102688033  inpp5a; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X2 [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
loc00010  Glycolysis / Gluconeogenesis
loc00061  Fatty acid biosynthesis
loc00500  Starch and sucrose metabolism
loc04010  MAPK signaling pathway
loc04070  Phosphatidylinositol signaling system
loc04210  Apoptosis
KO pathway
ko04910   
LinkDB

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