KEGG   PATHWAY: bspl04910
Entry
bspl04910                   Pathway                                
Name
Insulin signaling pathway - Betta splendens (Siamese fighting fish)
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
bspl04910  Insulin signaling pathway
bspl04910

Organism
Betta splendens (Siamese fighting fish) [GN:bspl]
Gene
114841906  mapk8a; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
114841921  eif4e1c; eukaryotic translation initiation factor 4E family member 1c [KO:K03259]
114841965  akt3a; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114842012  ppp1r3cb; protein phosphatase 1 regulatory subunit 3C-B [KO:K07189]
114842682  lipeb; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
114842943  flot1b; flotillin-1b isoform X1 [KO:K07192]
114843113  [KO:K07191]
114843588  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
114844025  insra; insulin receptor a [KO:K04527] [EC:2.7.10.1]
114844064  [KO:K02649]
114844327  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
114844354  [KO:K00922] [EC:2.7.1.153]
114844729  prkag3a; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
114844848  [KO:K07187]
114844854  rheb; GTP-binding protein Rheb isoform X1 [KO:K07208]
114844944  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
114844950  [KO:K05695] [EC:3.1.3.48]
114844983  [KO:K07200]
114845055  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
114845066  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
114845099  prkacbb; protein kinase, cAMP-dependent, catalytic, beta b [KO:K04345] [EC:2.7.11.11]
114845208  map2k2b; dual specificity mitogen-activated protein kinase kinase 2b [KO:K04369] [EC:2.7.12.2]
114845408  mapk8b; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
114845547  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
114845552  exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
114845646  araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
114845686  [KO:K04739]
114845715  pdpk1b; 3-phosphoinositide dependent protein kinase 1b isoform X1 [KO:K06276] [EC:2.7.11.1]
114845723  phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
114845825  socs3b; suppressor of cytokine signaling 3b [KO:K04696]
114845857  g6pc1a.2; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
114845858  [KO:K01084] [EC:3.1.3.9]
114845882  fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
114846051  [KO:K07189]
114846088  [KO:K06269] [EC:3.1.3.16]
114846348  [KO:K07187]
114846883  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
114847157  irs2b; insulin receptor substrate 2 [KO:K07187]
114847174  prkag3b; 5'-AMP-activated protein kinase subunit gamma-3b [KO:K07200]
114847347  [KO:K00688] [EC:2.4.1.1]
114847512  phka1a; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
114848177  eif4eb; eukaryotic translation initiation factor 4eb isoform X1 [KO:K03259]
114848630  sos2; son of sevenless homolog 2 [KO:K03099]
114848642  pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
114848934  akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114849035  calm1a; calmodulin-1a [KO:K02183]
114849214  calm1b; calmodulin-1b [KO:K02183]
114849913  [KO:K06269] [EC:3.1.3.16]
114851205  si:ch73-335l21.1; insulin receptor substrate 1-B isoform X2 [KO:K16172]
114851321  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
114851351  [KO:K06269] [EC:3.1.3.16]
114851687  [KO:K04688] [EC:2.7.11.1]
114851814  calml4a; calmodulin-like protein 4a [KO:K02183]
114851831  prkacab; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
114851859  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
114851913  phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
114851973  socs4; suppressor of cytokine signaling 4 [KO:K04697]
114852032  [KO:K07189]
114852122  [KO:K00844] [EC:2.7.1.1]
114852123  hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
114852131  phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
114852817  [KO:K04694]
114852871  [KO:K07200]
114853215  mknk2b; MAP kinase-interacting serine/threonine-protein kinase 2b isoform X1 [KO:K04372] [EC:2.7.11.1]
114853447  [KO:K00922] [EC:2.7.1.153]
114853520  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:2.7.12.2]
114853881  ptprfa; protein tyrosine phosphatase receptor type Fa isoform X1 [KO:K05695] [EC:3.1.3.48]
114854040  shc2; SHC-transforming protein 2 isoform X1 [KO:K17447]
114854048  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
114854090  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
114854235  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
114854454  prkacba; protein kinase, cAMP-dependent, catalytic, beta a isoform X2 [KO:K04345] [EC:2.7.11.11]
114854523  insrb; insulin receptor b [KO:K04527] [EC:2.7.10.1]
114854767  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) isoform X1 [KO:K02649]
114854785  [KO:K02649]
114855476  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
114855599  rhebl1; ras homolog, mTORC1 binding like 1 isoform X1 [KO:K07208]
114855824  prkar2ab; LOW QUALITY PROTEIN: protein kinase, cAMP-dependent, regulatory, type II, alpha, B [KO:K04739]
114856337  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
114856738  kras; GTPase KRas isoform X2 [KO:K07827]
114857221  [KO:K03099]
114857278  map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
114857388  [KO:K02833]
114857449  calml4b; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
114858281  raf1a; raf-1 proto-oncogene, serine/threonine kinase a isoform X1 [KO:K04366] [EC:2.7.11.1]
114858572  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
114858584  prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739]
114858626  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
114858652  ptpn1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
114858796  mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
114858922  elk1; ETS domain-containing protein Elk-1 [KO:K04375]
114859462  ppp1r3da; protein phosphatase 1, regulatory subunit 3Da [KO:K07189]
114860013  [KO:K01084] [EC:3.1.3.9]
114860075  [KO:K04739]
114860154  rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
114860300  grb2b; growth factor receptor-bound protein 2b [KO:K04364]
114860359  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
114860457  srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
114860476  tsc2; tuberin isoform X1 [KO:K07207]
114860511  trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196]
114860657  ppp1caa; protein phosphatase 1, catalytic subunit, alpha isozyme a [KO:K06269] [EC:3.1.3.16]
114860817  gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
114860844  socs1a; suppressor of cytokine signaling 1a [KO:K04694]
114860848  zgc:55558; GTPase KRas [KO:K07827]
114860968  socs3a; suppressor of cytokine signaling 3a [KO:K04696]
114861084  [KO:K00844] [EC:2.7.1.1]
114861092  prkacaa; protein kinase, cAMP-dependent, catalytic, alpha, genome duplicate a isoform X1 [KO:K04345] [EC:2.7.11.11]
114861320  gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
114861410  [KO:K02649]
114861413  ppp1r3aa; uncharacterized protein ppp1r3aa [KO:K07189]
114861429  tsc1a; TSC complex subunit 1a [KO:K07206]
114861505  braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
114861520  inpp5l; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
114861523  ppp1r3c2b; protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
114861570  [KO:K03841] [EC:3.1.3.11]
114861571  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
114861763  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit A [KO:K06269] [EC:3.1.3.16]
114861862  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
114861888  mapk1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
114861958  rps6; 40S ribosomal protein S6 [KO:K02991]
114861962  socs2; suppressor of cytokine signaling 2 [KO:K04695]
114862068  acacb; acetyl-CoA carboxylase isoform X4 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
114862241  eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
114862260  gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
114862600  hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
114862981  akt3b; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114863034  rapgef1a; rap guanine nucleotide exchange factor 1 [KO:K06277]
114863143  prkab1b; 5'-AMP-activated protein kinase subunit beta-1b [KO:K07199]
114863917  inppl1b; inositol polyphosphate phosphatase-like 1b isoform X1 [KO:K15909] [EC:3.1.3.86]
114864012  mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
114864471  [KO:K03259]
114864486  insb; preproinsulin b [KO:K04526]
114865425  lipea; lipase, hormone-sensitive a isoform X1 [KO:K07188] [EC:3.1.1.79]
114865679  badb; BCL2 associated agonist of cell death b [KO:K02158]
114866131  flot1a; flotillin-1a [KO:K07192]
114866487  rapgef1b; rap guanine nucleotide exchange factor 1b isoform X1 [KO:K06277]
114866513  [KO:K07205]
114866539  prkab1a; 5'-AMP-activated protein kinase subunit beta-1a [KO:K07199]
114866608  tsc1b; TSC complex subunit 1b isoform X1 [KO:K07206]
114866659  shc3; SHC-transforming protein 3 isoform X1 [KO:K17448]
114866688  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
114866713  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
114866785  [KO:K03259]
114867044  crkl; crk-like protein [KO:K04438]
114867198  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
114867343  ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
114867386  fbp1b; fructose-1,6-bisphosphatase 1b [KO:K03841] [EC:3.1.3.11]
114867769  [KO:K07192]
114867790  calm3a; calmodulin 3a (phosphorylase kinase, delta) [KO:K02183]
114867805  crk; adapter molecule crk [KO:K04438]
114867953  foxo1a; forkhead box protein O1-A [KO:K07201]
114867958  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
114867961  inppl1a; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2A isoform X1 [KO:K15909] [EC:3.1.3.86]
114867979  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
114868105  phkg1a; phosphorylase kinase, gamma 1a (muscle) [KO:K00871] [EC:2.7.11.19]
114868250  rps6kb1b; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
114868358  [KO:K07193]
114868391  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114869111  [KO:K07192]
114869214  cblb; E3 ubiquitin-protein ligase CBL-B-B isoform X1 [KO:K22517] [EC:2.3.2.27]
114869239  acaca; acetyl-CoA carboxylase 1 isoform X5 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
114869270  [KO:K04438]
114869279  [KO:K04456] [EC:2.7.11.1]
114869451  [KO:K00844] [EC:2.7.1.1]
114869494  rps6kb1a; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
114869594  si:ch211-284e13.4; insulin receptor substrate 1-B [KO:K16172]
114869661  [KO:K07201]
114869705  pygma; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
114869723  [KO:K04526]
114869891  ins; insulin isoform X1 [KO:K04526]
114869982  [KO:K04707] [EC:2.3.2.27]
114870356  [KO:K01106] [EC:3.1.3.56]
114870382  [KO:K07194]
114870415  [KO:K07196]
114870501  [KO:K06086]
114870598  calm2a; calmodulin 2a (phosphorylase kinase, delta) [KO:K02183]
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
bspl00010  Glycolysis / Gluconeogenesis
bspl00061  Fatty acid biosynthesis
bspl00500  Starch and sucrose metabolism
bspl04010  MAPK signaling pathway
bspl04070  Phosphatidylinositol signaling system
bspl04210  Apoptosis
KO pathway
ko04910   

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