KEGG   PATHWAY: mcep04910
Entry
mcep04910                   Pathway                                
Name
Insulin signaling pathway - Mugil cephalus (flathead mullet)
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
mcep04910  Insulin signaling pathway
mcep04910

Organism
Mugil cephalus (flathead mullet) [GN:mcep]
Gene
124995661  ppp1r3da; protein phosphatase 1, regulatory subunit 3Da [KO:K07189]
124995700  pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
124996387  pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
124996400  rapgef1b; rap guanine nucleotide exchange factor 1b isoform X1 [KO:K06277]
124996605  tsc1b; TSC complex subunit 1b isoform X1 [KO:K07206]
124996666  crkL; crk-like protein [KO:K04438]
124996813  prkab1a; 5'-AMP-activated protein kinase subunit beta-1a [KO:K07199]
124996844  prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
124996957  fbp1b; fructose-1,6-bisphosphatase 1b [KO:K03841] [EC:3.1.3.11]
124997018  mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
124997069  [KO:K07205]
124997099  shc3; SHC-transforming protein 3 [KO:K17448]
124997478  mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
124997520  gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
124997539  socs1a; suppressor of cytokine signaling 1a [KO:K04694]
124997541  zgc:55558; GTPase KRas [KO:K07827]
124997569  [KO:K04345] [EC:2.7.11.11]
124997688  ppp1caa; protein phosphatase 1, catalytic subunit, alpha isozyme A [KO:K06269] [EC:3.1.3.16]
124997850  srebf1; sterol regulatory element-binding protein 1 [KO:K07197]
124997906  prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
124998109  socs3a; suppressor of cytokine signaling 3a [KO:K04696]
124998162  [KO:K04364]
124998345  trip10a; cdc42-interacting protein 4 homolog isoform X1 [KO:K07196]
124998754  [KO:K06269] [EC:3.1.3.16]
124998844  [KO:K02183]
124999107  raf1a; raf-1 proto-oncogene, serine/threonine kinase A isoform X1 [KO:K04366] [EC:2.7.11.1]
125000036  braF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
125000304  socs2; suppressor of cytokine signaling 2 [KO:K04695]
125000355  ppp1r3aa; uncharacterized protein ppp1r3aa [KO:K07189]
125000453  gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
125000610  prkag3a; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
125000777  [KO:K07187]
125003436  [KO:K04345] [EC:2.7.11.11]
125003676  [KO:K03099]
125003690  [KO:K00844] [EC:2.7.1.1]
125003829  rps6; 40S ribosomal protein S6 [KO:K02991]
125004033  rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
125004186  [KO:K07196]
125004237  [KO:K04688] [EC:2.7.11.1]
125004240  tsc2; tuberin isoform X1 [KO:K07207]
125004256  pygmb; phosphorylase, glycogen, muscle B [KO:K00688] [EC:2.4.1.1]
125004283  [KO:K07189]
125004374  ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
125004613  akt3b; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
125004639  ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
125004650  [KO:K04694]
125005003  [KO:K02183]
125005130  [KO:K07189]
125005197  pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
125005205  [KO:K17449]
125005367  phkB; phosphorylase B kinase regulatory subunit beta isoform X1 [KO:K07190]
125005588  socs4; suppressor of cytokine signaling 4 [KO:K04697]
125005765  phka2; phosphorylase B kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
125006001  [KO:K00844] [EC:2.7.1.1]
125006002  [KO:K00844] [EC:2.7.1.1]
125006172  prkar2aa; protein kinase, cAMP-dependent, regulatory, type II, alpha A [KO:K04739]
125006180  mtoR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
125006593  [KO:K02183]
125006922  [KO:K07189]
125006978  rhebl1; ras homolog, mTORC1 binding like 1 [KO:K07208]
125007040  prkar2ab; protein kinase, cAMP-dependent, regulatory, type II, alpha, B [KO:K04739]
125007329  prkag1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
125007432  pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
125007653  [KO:K03259]
125007851  inppl1b; inositol polyphosphate phosphatase-like 1b [KO:K15909] [EC:3.1.3.86]
125008712  mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
125008716  insB; preproinsulin B [KO:K04526]
125008931  [KO:K04345] [EC:2.7.11.11]
125009018  mknk2b; MAP kinase-interacting serine/threonine-protein kinase 2b [KO:K04372] [EC:2.7.11.1]
125009089  elk1; ETS domain-containing protein Elk-1 [KO:K04375]
125009165  prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
125009281  pik3r3b; phosphoinositide-3-kinase, regulatory subunit 3b (gamma) [KO:K02649]
125009384  [KO:K00922] [EC:2.7.1.153]
125009454  map2k2a; dual specificity mitogen-activated protein kinase kinase 2a [KO:K04369] [EC:2.7.12.2]
125009551  insrb; insulin receptor B [KO:K04527] [EC:2.7.10.1]
125009643  mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
125009744  [KO:K02649]
125009776  shc2; SHC-transforming protein 2 isoform X1 [KO:K17447]
125009962  ptprfa; protein tyrosine phosphatase receptor type Fa isoform X1 [KO:K05695] [EC:3.1.3.48]
125009969  eif4e2rs1; eukaryotic translation initiation factor 4E family member 2 related sequence 1 [KO:K03259]
125010331  eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
125010352  rheB; GTP-binding protein Rheb [KO:K07208]
125010445  pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
125010514  [KO:K07200]
125010535  [KO:K04345] [EC:2.7.11.11]
125010558  prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
125010559  [KO:K05695] [EC:3.1.3.48]
125010560  [KO:K07187]
125010654  map2k2b; LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 2b [KO:K04369] [EC:2.7.12.2]
125010721  insra; insulin receptor A [KO:K04527] [EC:2.7.10.1]
125010793  [KO:K00922] [EC:2.7.1.153]
125010810  phka1a; phosphorylase B kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
125010829  prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
125011199  [KO:K02649]
125011846  prkab1b; 5'-AMP-activated protein kinase subunit beta-1b [KO:K07199]
125011855  acacb; acetyl-CoA carboxylase isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
125011866  ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
125012091  fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
125012106  mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
125012205  [KO:K07205]
125012239  hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
125012267  araF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
125012308  [KO:K06277]
125012328  gck; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
125012374  tsc1a; TSC complex subunit 1a isoform X1 [KO:K07206]
125012421  inpp5l; inositol polyphosphate-5-phosphatase A [KO:K01106] [EC:3.1.3.56]
125012477  ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit A [KO:K06269] [EC:3.1.3.16]
125012731  fbp1a; fructose-1,6-bisphosphatase 1a [KO:K03841] [EC:3.1.3.11]
125012779  [KO:K02649]
125012857  ppp1r3c2b; protein phosphatase 1 regulatory subunit 3C-B-like isoform X1 [KO:K07189]
125012876  badB; BCL2 associated agonist of cell death b isoform X1 [KO:K02158]
125012993  cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
125013116  foxo1a; forkhead box protein O1-A [KO:K07201]
125013316  calm3a; calmodulin 3a (phosphorylase kinase, delta) [KO:K02183]
125013336  pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
125013339  akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
125013379  crk; adapter molecule crk [KO:K04438]
125013387  inppl1a; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2A isoform X1 [KO:K15909] [EC:3.1.3.86]
125013413  phkg1a; phosphorylase kinase, gamma 1a (muscle) [KO:K00871] [EC:2.7.11.19]
125013416  [KO:K07193]
125013427  rps6kb1b; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
125013449  [KO:K07192]
125013716  [KO:K16172]
125014343  calml4b; calmodulin-like protein 4 [KO:K02183]
125014660  kraS; GTPase KRas [KO:K07827]
125015016  [KO:K02833]
125015166  map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
125015714  [KO:K06269] [EC:3.1.3.16]
125016060  shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
125016201  lipeb; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
125016289  flot1b; flotillin-1b [KO:K07192]
125017532  irs2b; insulin receptor substrate 2 [KO:K07187]
125017729  gsk3ba; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
125018059  prkag3b; 5'-AMP-activated protein kinase subunit gamma-3b isoform X1 [KO:K07200]
125018275  [KO:K01084] [EC:3.1.3.9]
125018435  [KO:K06086]
125018547  akt3a; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125018566  [KO:K01106] [EC:3.1.3.56]
125018600  [KO:K07189]
125018678  [KO:K07194]
125018763  calm2a; calmodulin 2a (phosphorylase kinase, delta) [KO:K02183]
125018810  eif4e1c; eukaryotic translation initiation factor 4E family member 1c [KO:K03259]
125019254  prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
125019343  mapk8a; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
125019514  [KO:K07191]
125020043  lipea; lipase, hormone-sensitive A [KO:K07188] [EC:3.1.1.79]
125020509  flot1a; flotillin-1a [KO:K07192]
125020738  acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
125020875  [KO:K04456] [EC:2.7.11.1]
125020921  [KO:K07192]
125021007  [KO:K16172]
125021073  pygma; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
125021079  rps6kb1a; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
125021087  [KO:K04438]
125021226  ins; insulin [KO:K04526]
125021255  [KO:K04707] [EC:2.3.2.27]
125021738  [KO:K07201]
125021820  [KO:K00844] [EC:2.7.1.1]
125021954  [KO:K04739]
125022122  mapk8b; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
125022132  g6pc1a.2; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
125022133  g6pc1a.1; glucose-6-phosphatase A, catalytic subunit, tandem duplicate 1 [KO:K01084] [EC:3.1.3.9]
125022245  pdpk1b; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
125022287  g6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
125022577  exoc7; exocyst complex component 7 [KO:K07195]
125022634  fasN; LOW QUALITY PROTEIN: fatty acid synthase [KO:K00665] [EC:2.3.1.85]
125022763  socs3b; suppressor of cytokine signaling 3b [KO:K04696]
125023011  [KO:K07189]
125023032  phkg2; phosphorylase B kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
125023156  pygL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
125023226  eif4eb; eukaryotic translation initiation factor 4eb [KO:K03259]
125023452  sos2; son of sevenless homolog 2 [KO:K03099]
125023675  akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125023722  [KO:K06269] [EC:3.1.3.16]
125024233  [KO:K02183]
125024403  pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
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
mcep00010  Glycolysis / Gluconeogenesis
mcep00061  Fatty acid biosynthesis
mcep00500  Starch and sucrose metabolism
mcep04010  MAPK signaling pathway
mcep04070  Phosphatidylinositol signaling system
mcep04210  Apoptosis
KO pathway
ko04910   

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