KEGG   PATHWAY: hsp04910
Entry
hsp04910                    Pathway                                
Name
Insulin signaling pathway - Hippoglossus stenolepis (Pacific halibut)
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
hsp04910  Insulin signaling pathway
hsp04910

Organism
Hippoglossus stenolepis (Pacific halibut) [GN:hsp]
Gene
118098019  shc3; SHC-transforming protein 3 [KO:K17448]
118098029  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118098368  [KO:K00844] [EC:2.7.1.1]
118098708  [KO:K07200]
118098793  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
118098902  akt3b; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118099217  calm1b; calmodulin-1b [KO:K02183]
118099407  [KO:K06269] [EC:3.1.3.16]
118100088  mapk8b; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118100245  pdpk1b; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
118100276  fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
118100390  g6pc3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
118100486  [KO:K06269] [EC:3.1.3.16]
118100498  exoc7; exocyst complex component 7 isoform X3 [KO:K07195]
118100551  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
118100630  [KO:K04739]
118100650  g6pc1a.2; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
118100683  g6pc1a.1; glucose-6-phosphatase a, catalytic subunit, tandem duplicate 1 [KO:K01084] [EC:3.1.3.9]
118100795  [KO:K04696]
118101128  [KO:K04694]
118101316  socs2; suppressor of cytokine signaling 2 [KO:K04695]
118101548  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
118101580  gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
118101884  ppp1r3aa; uncharacterized protein ppp1r3aa [KO:K07189]
118101924  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
118102247  [KO:K00688] [EC:2.4.1.1]
118102283  si:ch73-335l21.1; insulin receptor substrate 1-B isoform X2 [KO:K16172]
118102310  [KO:K07191]
118102525  badb; BCL2 associated agonist of cell death b [KO:K02158]
118102549  [KO:K07187]
118102638  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
118102789  [KO:K06269] [EC:3.1.3.16]
118102811  phka1a; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
118102841  eif4e2rs1; eukaryotic translation initiation factor 4E family member 2 related sequence 1 isoform X1 [KO:K03259]
118102955  [KO:K00922] [EC:2.7.1.153]
118103209  [KO:K07187]
118103337  prkag3a; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
118103784  flot1a; flotillin-1a isoform X1 [KO:K07192]
118104524  phkb; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
118104655  [KO:K04739]
118104758  ppp1r3db; protein phosphatase 1, regulatory subunit 3Db [KO:K07189]
118105150  [KO:K02183]
118105476  [KO:K07200]
118105477  rhebl1; ras homolog, mTORC1 binding like 1 [KO:K07208]
118105480  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
118105810  phkg1a; phosphorylase kinase, gamma 1a (muscle) [KO:K00871] [EC:2.7.11.19]
118105914  inppl1a; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2A isoform X1 [KO:K15909] [EC:3.1.3.86]
118105952  rps6kb1b; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
118106082  calm3a; calmodulin 3a (phosphorylase kinase, delta) [KO:K02183]
118106106  [KO:K00844] [EC:2.7.1.1]
118106128  [KO:K00844] [EC:2.7.1.1]
118106156  foxo1a; forkhead box protein O1-A [KO:K07201]
118106240  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118106261  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
118106304  crk; adapter molecule crk isoform X1 [KO:K04438]
118106320  [KO:K07193]
118106491  flot2b; flotillin-2b [KO:K07192]
118106564  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
118109259  kras; GTPase KRas isoform X1 [KO:K07827]
118109512  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
118109799  calml4b; calmodulin-like protein 4 isoform X1 [KO:K02183]
118109904  hrasb; HRas proto-oncogene, GTPase b [KO:K02833]
118110357  mtor; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
118110556  ppp1r3da; protein phosphatase 1, regulatory subunit 3Da [KO:K07189]
118110616  socs4; suppressor of cytokine signaling 4 [KO:K04697]
118110770  prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739]
118111080  elk1; ETS domain-containing protein Elk-3 isoform X1 [KO:K04375]
118111369  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
118111451  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
118111455  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
118111456  raf1a; raf-1 proto-oncogene, serine/threonine kinase a isoform X1 [KO:K04366] [EC:2.7.11.1]
118111558  ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
118111608  si:ch211-167b20.8; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
118111614  calml4a; calmodulin-like protein 4a [KO:K02183]
118111847  eif4ea; eukaryotic translation initiation factor 4E-1A isoform X1 [KO:K03259]
118112055  inppl1b; inositol polyphosphate phosphatase-like 1b isoform X1 [KO:K15909] [EC:3.1.3.86]
118112070  mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
118112301  [KO:K07189]
118112388  [KO:K04526]
118113210  flot1b; flotillin-1b isoform X1 [KO:K07192]
118113543  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118113590  lipeb; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
118114578  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
118114623  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
118114645  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
118114652  acacb; acetyl-CoA carboxylase isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118114670  tsc1a; TSC complex subunit 1a isoform X1 [KO:K07206]
118114686  [KO:K02649]
118114727  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
118114879  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit A [KO:K06269] [EC:3.1.3.16]
118115008  [KO:K07205]
118115011  hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
118115119  ppp1r3c2b; protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
118115140  gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
118115377  prkab1b; 5'-AMP-activated protein kinase subunit beta-1b isoform X1 [KO:K07199]
118115461  inpp5l; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
118115539  fbp1a; fructose-1,6-bisphosphatase 1a [KO:K03841] [EC:3.1.3.11]
118115889  calm1a; calmodulin-1a [KO:K02183]
118116198  eif4eb; LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4eb [KO:K03259]
118116209  akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118116327  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
118116347  [KO:K07196]
118116488  [KO:K06269] [EC:3.1.3.16]
118116998  sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118117188  [KO:K07200]
118117258  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
118117356  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
118117868  [KO:K00922] [EC:2.7.1.153]
118117870  prkacbb; protein kinase, cAMP-dependent, catalytic, beta b isoform X1 [KO:K04345] [EC:2.7.11.11]
118117905  [KO:K02649]
118117936  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118117990  [KO:K05695] [EC:3.1.3.48]
118117994  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
118118019  insra; insulin receptor a isoform X1 [KO:K04527] [EC:2.7.10.1]
118118306  tsc2; tuberin isoform X1 [KO:K07207]
118118332  rheb; GTP-binding protein Rheb [KO:K07208]
118118580  [KO:K06086]
118118682  [KO:K07194]
118118820  calm2a; calmodulin 2a (phosphorylase kinase, delta) [KO:K02183]
118118847  mapk8a; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118118965  akt3a; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118119063  eif4e1c; eukaryotic translation initiation factor 4E family member 1c [KO:K03259]
118119236  [KO:K07189]
118119362  [KO:K01106] [EC:3.1.3.56]
118119692  prkag3b; 5'-AMP-activated protein kinase subunit gamma-3b [KO:K07200]
118119791  gsk3ba; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
118119877  irs2b; insulin receptor substrate 2 [KO:K07187]
118120147  [KO:K01084] [EC:3.1.3.9]
118120279  [KO:K03099]
118120705  mknk2b; MAP kinase-interacting serine/threonine-protein kinase 2b [KO:K04372] [EC:2.7.11.1]
118120708  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
118120869  insrb; insulin receptor b [KO:K04527] [EC:2.7.10.1]
118120902  [KO:K02649]
118120944  shc2; SHC-transforming protein 2 [KO:K17447]
118120979  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) isoform X1 [KO:K02649]
118121033  [KO:K00922] [EC:2.7.1.153]
118121192  [KO:K04688] [EC:2.7.11.1]
118121305  prkacba; protein kinase, cAMP-dependent, catalytic, beta a isoform X1 [KO:K04345] [EC:2.7.11.11]
118121396  ptprfa; protein tyrosine phosphatase receptor type Fa [KO:K05695] [EC:3.1.3.48]
118121798  [KO:K17449]
118121829  pygma; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
118121843  [KO:K07192]
118121874  [KO:K04438]
118121900  [KO:K04456] [EC:2.7.11.1]
118122026  acaca; acetyl-CoA carboxylase 1 isoform X3 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118122079  rps6kb1a; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
118122095  [KO:K04707] [EC:2.3.2.27]
118122248  ins; insulin [KO:K04526]
118122591  [KO:K00844] [EC:2.7.1.1]
118122658  cblb; E3 ubiquitin-protein ligase CBL-B-B [KO:K22517] [EC:2.3.2.27]
118122982  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
118123198  prkar1aa; protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1) a isoform X1 [KO:K04739]
118123233  prkacaa; protein kinase, cAMP-dependent, catalytic, alpha, genome duplicate a isoform X1 [KO:K04345] [EC:2.7.11.11]
118123236  trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196]
118123348  [KO:K04345] [EC:2.7.11.11]
118123399  srebf1; sterol regulatory element-binding protein 1 isoform X3 [KO:K07197]
118123457  ppp1caa; protein phosphatase 1, catalytic subunit, alpha isozyme a [KO:K06269] [EC:3.1.3.16]
118123543  rps6; 40S ribosomal protein S6 [KO:K02991]
118123567  grb2b; growth factor receptor-bound protein 2b isoform X1 [KO:K04364]
118123856  gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
118123859  zgc:55558; GTPase KRas isoform X1 [KO:K07827]
118123896  socs3a; suppressor of cytokine signaling 3a [KO:K04696]
118123906  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
118123914  socs1a; suppressor of cytokine signaling 1a [KO:K04694]
118125101  lipea; lipase, hormone-sensitive a isoform X1 [KO:K07188] [EC:3.1.1.79]
118125392  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118125467  rapgef1b; rap guanine nucleotide exchange factor 1b isoform X1 [KO:K06277]
118125489  prkab1a; 5'-AMP-activated protein kinase subunit beta-1a isoform X1 [KO:K07199]
118125634  rptor; LOW QUALITY PROTEIN: regulatory-associated protein of mTOR [KO:K07204]
118125678  crkl; crk-like protein [KO:K04438]
118125713  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
118125727  [KO:K07205]
118125787  fbp1b; fructose-1,6-bisphosphatase 1b [KO:K03841] [EC:3.1.3.11]
118125796  tsc1b; TSC complex subunit 1b [KO:K07206]
118125889  ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
124854736  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:2.7.12.2]
124854779  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
124854838  si:ch211-284e13.4; insulin receptor substrate 1-B [KO:K16172]
124854860  [KO:K07201]
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
hsp00010  Glycolysis / Gluconeogenesis
hsp00061  Fatty acid biosynthesis
hsp00500  Starch and sucrose metabolism
hsp04010  MAPK signaling pathway
hsp04070  Phosphatidylinositol signaling system
hsp04210  Apoptosis
KO pathway
ko04910   

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