KEGG   PATHWAY: hhip04910
Entry
hhip04910                   Pathway                                
Name
Insulin signaling pathway - Hippoglossus hippoglossus (Atlantic 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
hhip04910  Insulin signaling pathway
hhip04910

Organism
Hippoglossus hippoglossus (Atlantic halibut) [GN:hhip]
Gene
117751801  [KO:K06269] [EC:3.1.3.16]
117751826  [KO:K07187]
117751949  phka1a; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
117752018  socs4; suppressor of cytokine signaling 4 [KO:K04697]
117752039  si:ch73-335l21.1; LOW QUALITY PROTEIN: insulin receptor substrate 1-B [KO:K16172]
117752058  [KO:K07191]
117752269  badb; BCL2 associated agonist of cell death b [KO:K02158]
117752542  mapk8b; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
117752552  [KO:K04739]
117752749  ppp1cab; protein phosphatase 1, catalytic subunit, alpha isozyme b isoform X1 [KO:K06269] [EC:3.1.3.16]
117752846  g6pca.2; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
117752848  g6pca.1; glucose-6-phosphatase a, catalytic subunit, tandem duplicate 1 [KO:K01084] [EC:3.1.3.9]
117752999  phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
117753024  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
117753080  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
117753126  exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
117753191  fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
117753308  [KO:K04696]
117753368  pdpk1b; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
117753907  [KO:K07200]
117753963  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
117754755  [KO:K01084] [EC:3.1.3.9]
117755348  irs2b; insulin receptor substrate 2 [KO:K07187]
117755388  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
117755406  [KO:K00844] [EC:2.7.1.1]
117755419  [KO:K00844] [EC:2.7.1.1]
117755469  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
117755516  [KO:K06269] [EC:3.1.3.16]
117755641  akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117755803  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
117755890  calm1a; calmodulin-1a [KO:K02183]
117756187  calml4a; calmodulin-like protein 4a [KO:K02183]
117756630  eif4eb; eukaryotic translation initiation factor 4eb isoform X1 [KO:K03259]
117756659  sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
117757357  gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
117757425  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
117757526  ppp1r3aa; uncharacterized protein ppp1r3aa isoform X1 [KO:K07189]
117757607  socs2; suppressor of cytokine signaling 2 [KO:K04695]
117757626  [KO:K07189]
117758526  [KO:K06269] [EC:3.1.3.16]
117758839  calm1b; calmodulin-1b [KO:K02183]
117759210  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
117759303  [KO:K17449]
117759678  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:2.7.12.2]
117759730  mknk2b; MAP kinase-interacting serine/threonine-protein kinase 2b [KO:K04372] [EC:2.7.11.1]
117759920  prkacba; protein kinase, cAMP-dependent, catalytic, beta a isoform X1 [KO:K04345] [EC:2.7.11.11]
117759963  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
117760130  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) isoform X1 [KO:K02649]
117760503  [KO:K00922] [EC:2.7.1.153]
117760625  [KO:K02649]
117760639  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
117760725  insrb; LOW QUALITY PROTEIN: insulin receptor b [KO:K04527] [EC:2.7.10.1]
117760743  shc2; SHC-transforming protein 2 isoform X1 [KO:K17447]
117760756  ptprfa; protein tyrosine phosphatase receptor type Fa isoform X1 [KO:K05695] [EC:3.1.3.48]
117761288  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
117761290  rhebl1; ras homolog, mTORC1 binding like 1 [KO:K07208]
117761378  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
117761555  ppp1r3db; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
117761634  [KO:K02183]
117761826  prkar2ab; protein kinase, cAMP-dependent, regulatory, type II, alpha, B isoform X1 [KO:K04739]
117762987  kras; GTPase KRas isoform X1 [KO:K07827]
117763104  map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
117763291  calml4b; calmodulin-like protein 4 [KO:K02183]
117763559  [KO:K03099]
117763573  [KO:K02833]
117763790  [KO:K04739]
117764087  akt3b; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117764306  elk1; ETS domain-containing protein Elk-3 [KO:K04375]
117764442  mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
117764453  si:ch211-167b20.8; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
117764604  ppp1r3da; protein phosphatase 1, regulatory subunit 3Da [KO:K07189]
117764692  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
117764706  [KO:K05696] [EC:3.1.3.48]
117764958  [KO:K04694]
117765043  [KO:K04688] [EC:2.7.11.1]
117765132  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
117765330  raf1a; raf-1 proto-oncogene, serine/threonine kinase a isoform X1 [KO:K04366] [EC:2.7.11.1]
117765356  prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739]
117765696  prkacaa; protein kinase, cAMP-dependent, catalytic, alpha, genome duplicate a isoform X1 [KO:K04345] [EC:2.7.11.11]
117765770  socs3a; suppressor of cytokine signaling 3a [KO:K04696]
117765821  prkar1aa; protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1) a isoform X1 [KO:K04739]
117765884  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
117765896  socs1a; suppressor of cytokine signaling 1a [KO:K04694]
117766447  trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196]
117766449  grb2b; growth factor receptor-bound protein 2b isoform X1 [KO:K04364]
117766729  gys1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
117766747  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
117766775  zgc:55558; GTPase HRas [KO:K07827]
117766826  rps6; 40S ribosomal protein S6 [KO:K02991]
117766844  ppp1caa; protein phosphatase 1, catalytic subunit, alpha isozyme a [KO:K06269] [EC:3.1.3.16]
117766863  srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
117767207  gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
117767355  prkab1b; 5'-AMP-activated protein kinase subunit beta-1b [KO:K07199]
117767497  inpp5l; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
117767659  acacb; LOW QUALITY PROTEIN: acetyl-CoA carboxylase [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
117767714  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
117767832  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
117767951  rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
117767957  hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
117767997  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
117768103  fbp1a; fructose-1,6-bisphosphatase 1a [KO:K03841] [EC:3.1.3.11]
117768104  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
117768198  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit A [KO:K06269] [EC:3.1.3.16]
117768329  zgc:77112; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
117768381  [KO:K02649]
117768487  tsc2; tuberin isoform X1 [KO:K07207]
117768511  [KO:K07205]
117768560  tsc1a; TSC complex subunit 1a isoform X1 [KO:K07206]
117769057  [KO:K00844] [EC:2.7.1.1]
117769257  mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
117769264  insb; preproinsulin b [KO:K04526]
117769562  inppl1b; inositol polyphosphate phosphatase-like 1b isoform X1 [KO:K15909] [EC:3.1.3.86]
117769593  [KO:K03259]
117770234  lipea; lipase, hormone-sensitive a isoform X1 [KO:K07188] [EC:3.1.1.79]
117770387  [KO:K07196]
117770967  flot1a; flotillin-1a [KO:K07192]
117771209  prkab1a; 5'-AMP-activated protein kinase subunit beta-1a isoform X1 [KO:K07199]
117771255  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
117771278  shc3; SHC-transforming protein 3 [KO:K17448]
117771370  ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
117771452  [KO:K07205]
117771521  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
117771524  rapgef1b; rap guanine nucleotide exchange factor 1b isoform X1 [KO:K06277]
117771643  crkl; crk-like protein [KO:K04438]
117771698  tsc1b; TSC complex subunit 1b isoform X1 [KO:K07206]
117772091  fbp1b; fructose-1,6-bisphosphatase 1b [KO:K03841] [EC:3.1.3.11]
117772227  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
117772327  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117772555  crk; adapter molecule crk [KO:K04438]
117772697  rps6kb1b; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
117772722  [KO:K07193]
117772752  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
117772853  inppl1a; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2A [KO:K15909] [EC:3.1.3.86]
117772879  foxo1a; forkhead box protein O1-A [KO:K07201]
117772967  cbl; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
117773197  calm3a; calmodulin 3a (phosphorylase kinase, delta) [KO:K02183]
117773232  phkg1a; phosphorylase kinase, gamma 1a (muscle) [KO:K00871] [EC:2.7.11.19]
117773983  [KO:K04707] [EC:2.3.2.27]
117774045  [KO:K07192]
117774049  [KO:K07187]
117774099  rps6kb1a; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
117774385  [KO:K00844] [EC:2.7.1.1]
117774475  acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
117774495  si:ch211-284e13.4; insulin receptor substrate 1-B [KO:K16172]
117774511  cblb; E3 ubiquitin-protein ligase CBL-B-B [KO:K22517] [EC:2.3.2.27]
117774515  [KO:K04456] [EC:2.7.11.1]
117774528  pygma; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
117774549  [KO:K04438]
117774639  ins; insulin [KO:K04526]
117774873  [KO:K07201]
117775031  [KO:K06086]
117775046  ppp1r3cb; protein phosphatase 1 regulatory subunit 3C-B [KO:K07189]
117775103  eif4e1c; eukaryotic translation initiation factor 4E family member 1c isoform X1 [KO:K03259]
117775231  akt3a; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117775240  calm2a; calmodulin 2a (phosphorylase kinase, delta) [KO:K02183]
117775372  [KO:K01106] [EC:3.1.3.56]
117775403  [KO:K07194]
117775780  mapk8a; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
117776519  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
117776811  flot1b; flotillin-1b [KO:K07192]
117777476  prkag3a; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
117777502  lipeb; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
117777997  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
117778034  [KO:K00922] [EC:2.7.1.153]
117778066  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
117778097  rheb; GTP-binding protein Rheb [KO:K07208]
117778159  [KO:K02649]
117778453  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
117778456  [KO:K07200]
117778848  insra; insulin receptor a isoform X1 [KO:K04527] [EC:2.7.10.1]
117778855  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
117778858  [KO:K05695] [EC:3.1.3.48]
117778886  prkacbb; protein kinase, cAMP-dependent, catalytic, beta b isoform X1 [KO:K04345] [EC:2.7.11.11]
117779165  [KO:K00688] [EC:2.4.1.1]
117779227  zgc:158659; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
117779240  eif4e2rs1; eukaryotic translation initiation factor 4E family member 2 related sequence 1 [KO:K03259]
117779381  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
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
hhip00010  Glycolysis / Gluconeogenesis
hhip00061  Fatty acid biosynthesis
hhip00500  Starch and sucrose metabolism
hhip04010  MAPK signaling pathway
hhip04070  Phosphatidylinositol signaling system
hhip04210  Apoptosis
KO pathway
ko04910   

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