KEGG   PATHWAY: xgl04910
Entry
xgl04910                    Pathway                                
Name
Insulin signaling pathway - Xiphias gladius (swordfish)
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
xgl04910  Insulin signaling pathway
xgl04910

Organism
Xiphias gladius (swordfish) [GN:xgl]
Gene
120782943  hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
120782944  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
120783055  trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196]
120783422  prkar2ab; LOW QUALITY PROTEIN: protein kinase, cAMP-dependent, regulatory, type II, alpha, B [KO:K04739]
120783842  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
120784102  flot1b; flotillin-1b [KO:K07192]
120784156  lipeb; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
120784329  prkacaa; protein kinase, cAMP-dependent, catalytic, alpha, genome duplicate a isoform X1 [KO:K04345] [EC:2.7.11.11]
120785027  srebf1; sterol regulatory element-binding protein 1 [KO:K07197]
120785361  [KO:K03259]
120785433  mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
120785491  inppl1b; inositol polyphosphate phosphatase-like 1b isoform X1 [KO:K15909] [EC:3.1.3.86]
120785499  insb; preproinsulin b [KO:K04526]
120785759  ppp1caa; protein phosphatase 1, catalytic subunit, alpha isozyme a [KO:K06269] [EC:3.1.3.16]
120786287  flot1a; flotillin-1a isoform X1 [KO:K07192]
120786533  [KO:K01084] [EC:3.1.3.9]
120786574  lipea; lipase, hormone-sensitive a [KO:K07188] [EC:3.1.1.79]
120786748  prkar1aa; protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1) a isoform X1 [KO:K04739]
120787511  [KO:K06277]
120788168  grb2b; growth factor receptor-bound protein 2b [KO:K04364]
120788348  socs3a; suppressor of cytokine signaling 3a [KO:K04696]
120788409  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
120788720  calm1b; calmodulin-1b [KO:K02183]
120788837  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
120788951  [KO:K06269] [EC:3.1.3.16]
120789744  [KO:K07200]
120789787  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
120790651  shc2; SHC-transforming protein 2 isoform X1 [KO:K17447]
120790713  [KO:K02649]
120790754  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
120790764  prkacba; protein kinase, cAMP-dependent, catalytic, beta a isoform X1 [KO:K04345] [EC:2.7.11.11]
120790856  mknk2b; MAP kinase-interacting serine/threonine-protein kinase 2b [KO:K04372] [EC:2.7.11.1]
120790940  mknk1; LOW QUALITY PROTEIN: MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
120791009  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:2.7.12.2]
120791111  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) isoform X1 [KO:K02649]
120791188  insrb; insulin receptor b isoform X1 [KO:K04527] [EC:2.7.10.1]
120791340  [KO:K00922] [EC:2.7.1.153]
120791360  ptprfa; protein tyrosine phosphatase receptor type Fa isoform X1 [KO:K05695] [EC:3.1.3.48]
120791493  [KO:K00871] [EC:2.7.11.19]
120791753  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
120791765  inppl1a; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2A [KO:K15909] [EC:3.1.3.86]
120791860  crk; adapter molecule crk [KO:K04438]
120791894  akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
120791906  foxo1a; forkhead box protein O1-A [KO:K07201]
120791909  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
120791911  phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
120791971  calm3a; calmodulin 3a (phosphorylase kinase, delta) [KO:K02183]
120792101  [KO:K17449]
120792170  [KO:K04688] [EC:2.7.11.1]
120792395  [KO:K07192]
120792463  [KO:K07193]
120792735  [KO:K02833]
120792900  [KO:K07189]
120793060  [KO:K04739]
120793090  calml4b; calmodulin-like protein 4 [KO:K02183]
120793562  map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
120793826  kras; GTPase KRas isoform X1 [KO:K07827]
120794103  socs3b; suppressor of cytokine signaling 3b [KO:K04696]
120794114  fasn; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
120794168  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
120794179  ppp1cab; protein phosphatase 1, catalytic subunit, alpha isozyme b [KO:K06269] [EC:3.1.3.16]
120794290  [KO:K07189]
120794363  [KO:K04739]
120794394  mapk8b; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
120794418  g6pc1a.2; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
120794419  [KO:K01084] [EC:3.1.3.9]
120794450  socs4; suppressor of cytokine signaling 4 [KO:K04697]
120794484  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
120794611  pdpk1b; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
120794855  exoc7; LOW QUALITY PROTEIN: exocyst complex component 7 [KO:K07195]
120795055  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
120795056  eif4eb; eukaryotic translation initiation factor 4eb [KO:K03259]
120795095  [KO:K06269] [EC:3.1.3.16]
120795148  [KO:K02183]
120795180  calm1a; calmodulin-1a [KO:K02183]
120795320  akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
120795329  sos2; son of sevenless homolog 2 [KO:K03099]
120795358  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
120796033  eif4e1c; eukaryotic translation initiation factor 4E family member 1c isoform X1 [KO:K03259]
120796205  mapk8a; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
120796314  rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
120796399  pygb; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
120796415  [KO:K06086]
120796417  calm2a; calmodulin 2a (phosphorylase kinase, delta) [KO:K02183]
120796548  [KO:K01106] [EC:3.1.3.56]
120796885  akt3a; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
120796943  ppp1r3ca; protein phosphatase 1, regulatory subunit 3Ca [KO:K07189]
120797016  [KO:K00922] [EC:2.7.1.153]
120797028  [KO:K06269] [EC:3.1.3.16]
120797165  phka1a; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
120797346  [KO:K00688] [EC:2.4.1.1]
120797372  badb; BCL2 associated agonist of cell death b [KO:K02158]
120797377  si:ch73-335l21.1; LOW QUALITY PROTEIN: insulin receptor substrate 1-B [KO:K16172]
120797420  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
120797472  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
120797611  [KO:K07191]
120797616  eif4e2rs1; eukaryotic translation initiation factor 4E family member 2 related sequence 1 isoform X1 [KO:K03259]
120797646  [KO:K07187]
120797905  prkag3a; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
120798246  [KO:K07187]
120798578  insra; insulin receptor a [KO:K04527] [EC:2.7.10.1]
120798627  map2k2b; dual specificity mitogen-activated protein kinase kinase 2b [KO:K04369] [EC:2.7.12.2]
120798643  [KO:K05695] [EC:3.1.3.48]
120798719  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
120798758  [KO:K07200]
120798952  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
120799023  [KO:K00922] [EC:2.7.1.153]
120799080  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
120799119  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
120799292  prkacbb; protein kinase, cAMP-dependent, catalytic, beta b isoform X1 [KO:K04345] [EC:2.7.11.11]
120799345  [KO:K07208]
120799460  [KO:K02649]
120799682  [KO:K07196]
120799730  [KO:K04694]
120799911  rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
120799916  rps6; 40S ribosomal protein S6 [KO:K02991]
120799938  tsc2; tuberin isoform X1 [KO:K07207]
120799943  akt3b; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
120800006  [KO:K04688] [EC:2.7.11.1]
120800055  [KO:K00844] [EC:2.7.1.1]
120800238  [KO:K03099]
120800956  prkacab; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
120801245  irs2b; insulin receptor substrate 2 [KO:K07187]
120801297  [KO:K01084] [EC:3.1.3.9]
120801334  socs2; suppressor of cytokine signaling 2 [KO:K04695]
120801452  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
120801480  prkag3b; 5'-AMP-activated protein kinase subunit gamma-3b [KO:K07200]
120802074  cblb; E3 ubiquitin-protein ligase CBL-B-B isoform X1 [KO:K22517] [EC:2.3.2.27]
120802170  si:ch211-284e13.4; insulin receptor substrate 1-B [KO:K16172]
120802301  [KO:K04707] [EC:2.3.2.27]
120802434  rps6kb1a; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
120802629  gys2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
120802771  [KO:K07201]
120802773  [KO:K04526]
120802802  [KO:K04526]
120802926  [KO:K04456] [EC:2.7.11.1]
120803001  acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
120803007  [KO:K04438]
120803049  [KO:K00844] [EC:2.7.1.1]
120803051  [KO:K00688] [EC:2.4.1.1]
120803064  [KO:K07192]
120803375  raf1a; raf-1 proto-oncogene, serine/threonine kinase a isoform X1 [KO:K04366] [EC:2.7.11.1]
120803398  elk1; LOW QUALITY PROTEIN: ETS domain-containing protein Elk-1 [KO:K04375]
120803584  [KO:K07189]
120803615  mtor; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
120803702  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
120803903  prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739]
120804015  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
120804039  si:ch211-167b20.8; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
120804101  ppp1r3da; protein phosphatase 1, regulatory subunit 3Da isoform X1 [KO:K07189]
120804136  ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
120804182  ppp1r3aa; uncharacterized protein ppp1r3aa isoform X1 [KO:K07189]
120804708  [KO:K03841] [EC:3.1.3.11]
120804922  tsc1a; TSC complex subunit 1a isoform X1 [KO:K07206]
120804982  inpp5l; inositol polyphosphate-5-phosphatase A isoform X1 [KO:K01106] [EC:3.1.3.56]
120805057  [KO:K02649]
120805086  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
120805150  hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
120805159  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
120805165  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
120805335  gck; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
120805339  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
120805460  zgc:77112; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3C [KO:K07189]
120805566  acacb; acetyl-CoA carboxylase isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
120805583  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit A [KO:K06269] [EC:3.1.3.16]
120805681  prkab1b; 5'-AMP-activated protein kinase subunit beta-1b [KO:K07199]
120805785  socs1a; suppressor of cytokine signaling 1a [KO:K04694]
120805843  [KO:K07205]
120806119  fbp1b; fructose-1,6-bisphosphatase 1b [KO:K03841] [EC:3.1.3.11]
120806176  [KO:K07205]
120806202  rapgef1b; rap guanine nucleotide exchange factor 1b isoform X1 [KO:K06277]
120806252  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
120806310  crkl; crk-like protein [KO:K04438]
120806359  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
120806376  tsc1b; TSC complex subunit 1b isoform X1 [KO:K07206]
120806505  prkab1a; 5'-AMP-activated protein kinase subunit beta-1a isoform X1 [KO:K07199]
120806506  [KO:K07827]
120806618  si:dkey-242g16.2; protein phosphatase 1 regulatory subunit 3C-B [KO:K07189]
120806701  shc3; SHC-transforming protein 3 [KO:K17448]
120806753  mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
120806777  ppp1r3b; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
120806935  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
120807298  ppp1r3db; protein phosphatase 1, regulatory subunit 3Db [KO:K07189]
120807405  [KO:K07200]
120807406  rhebl1; ras homolog, mTORC1 binding like 1 isoform X1 [KO:K07208]
120807501  [KO:K02183]
120807561  gys1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
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
xgl00010  Glycolysis / Gluconeogenesis
xgl00061  Fatty acid biosynthesis
xgl00500  Starch and sucrose metabolism
xgl04010  MAPK signaling pathway
xgl04070  Phosphatidylinositol signaling system
xgl04210  Apoptosis
KO pathway
ko04910   

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