KEGG   PATHWAY: nmel04910
Entry
nmel04910                   Pathway                                
Name
Insulin signaling pathway - Numida meleagris (helmeted guineafowl)
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
nmel04910  Insulin signaling pathway
nmel04910

Organism
Numida meleagris (helmeted guineafowl) [GN:nmel]
Gene
110400779  INS; insulin [KO:K04526]
110389023  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
110397421  IRS1; insulin receptor substrate 1 [KO:K16172]
110403269  IRS4; insulin receptor substrate 4 [KO:K07187]
110391172  insulin receptor substrate 2-like [KO:K07187]
110407441  IRS2; insulin receptor substrate 2 [KO:K07187]
110389564  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110388756  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
110402756  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
110398160  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
110397252  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
110408755  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
110405647  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
110396620  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110400745  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110399222  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
110396288  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
110400859  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
110396314  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
110406337  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
110387098  protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
110398572  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
110400325  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
110392303  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
110408137  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
110404563  protein phosphatase 1 regulatory subunit 3E-like [KO:K07189]
110407838  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
110403030  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
110404225  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
110404712  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
110403952  CALML4; calmodulin-like protein 4 [KO:K02183]
110396315  CALM2; calmodulin-2 [KO:K02183]
110401188  CALM1; calmodulin-1 [KO:K02183]
110392216  calmodulin, striated muscle [KO:K02183]
110395559  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
110401574  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
110401246  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
110402971  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
110407201  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
110404838  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
110405992  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
110392375  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
110408649  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
110397778  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
110407704  FLOT2; flotillin-2 isoform X1 [KO:K07192]
110407624  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
110399490  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
110387634  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
110400575  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
110406265  CRKL; crk-like protein [KO:K04438]
110407619  CRK; adapter molecule crk isoform X1 [KO:K04438]
110406774  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
110395488  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
110407281  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
110405878  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
110407726  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
110406566  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
110407258  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
110387156  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
110405141  hexokinase-3-like isoform X1 [KO:K00844] [EC:2.7.1.1]
110399272  hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
110399274  putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
110387119  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
110402720  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
110389430  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
110406386  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
110402546  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
110389185  5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
110394133  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
110400535  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
110388188  FOXO1; forkhead box protein O1 [KO:K07201]
110398248  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
110388500  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
110399581  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
110388560  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
110390078  fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
110390208  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
110408320  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
110408585  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
110407207  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
110407933  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
110390047  RPS6; 40S ribosomal protein S6 [KO:K02991]
110387062  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 isoform X1 [KO:K07205]
110397760  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
110405362  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
110398052  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
110406741  TSC1; hamartin isoform X1 [KO:K07206]
110406041  TSC2; tuberin isoform X1 [KO:K07207]
110394136  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
110391258  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
110389019  SHC2; SHC-transforming protein 2 [KO:K17447]
110390178  SHC3; SHC-transforming protein 3 [KO:K17448]
110403695  SHC4; SHC-transforming protein 4 [KO:K17449]
110407421  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
110401960  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
110397177  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
110400761  HRAS; GTPase HRas [KO:K02833]
110396332  KRAS; GTPase KRas isoform X1 [KO:K07827]
110388133  NRAS; GTPase NRas [KO:K07828]
110394457  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
110404723  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
110404031  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
110388854  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
110406180  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
110402608  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
110388793  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
110405695  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
110393037  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
110407470  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
110401367  SOCS4; suppressor of cytokine signaling 4 isoform X1 [KO:K04697]
110408156  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
110402858  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
110398630  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
110405490  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
110399325  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
110387184  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
110403391  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like isoform X1 [KO:K15909] [EC:3.1.3.86]
110391676  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
110399478  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [KO:K01106] [EC:3.1.3.56]
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
nmel00010  Glycolysis / Gluconeogenesis
nmel00061  Fatty acid biosynthesis
nmel00500  Starch and sucrose metabolism
nmel04010  MAPK signaling pathway
nmel04070  Phosphatidylinositol signaling system
nmel04210  Apoptosis
KO pathway
ko04910   
LinkDB

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