KEGG   PATHWAY: mmea04910
Entry
mmea04910                   Pathway                                
Name
Insulin signaling pathway - Malurus melanocephalus (red-backed fairy wren)
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
mmea04910  Insulin signaling pathway
mmea04910

Organism
Malurus melanocephalus (red-backed fairy wren) [GN:mmea]
Gene
130577075  INS; insulin [KO:K04526]
130585531  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
130573986  IRS1; insulin receptor substrate 1 [KO:K16172]
130588974  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
130573325  insulin receptor substrate 2-A-like [KO:K07187]
130586288  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
130572286  phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
130582513  phosphatidylinositol 3-kinase regulatory subunit alpha-like isoform X1 [KO:K02649]
130589279  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
130581543  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
130579313  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
130580167  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
130576467  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
130587587  RAC-beta serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
130588807  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
130584616  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
130579446  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
130576128  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
130580351  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
130576505  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
130580061  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
130580550  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
130577285  protein phosphatase 1 regulatory subunit 3E-like [KO:K07189]
130589220  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
130584491  protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
130579581  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
130586018  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
130586087  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
130578730  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
130579103  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
130576160  CALM1; calmodulin-1 [KO:K02183]
130576515  CALM2; calmodulin-2 [KO:K02183]
130577132  CALML4; calmodulin-like protein 4 [KO:K02183]
130588221  calmodulin, striated muscle-like [KO:K02183]
130581293  glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
130584190  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
130575645  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
130578641  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
130572677  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
130589156  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
130583112  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
130584180  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
130583439  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
130575487  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
130576976  FLOT2; flotillin-2 isoform X1 [KO:K07192]
130577767  SH2B2; SH2B adapter protein 2 [KO:K07193]
130579912  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
130584689  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
130578085  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
130586163  CRK; adapter molecule crk isoform X1 [KO:K04438]
130578027  CRKL; crk-like protein [KO:K04438]
130576724  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
130578216  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
130581049  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
130582528  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
130583719  ACACA; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
130580515  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
130581978  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
130580795  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
130577982  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
130577997  hexokinase HKDC1-like [KO:K00844] [EC:2.7.1.1]
130584457  hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
130585276  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
130572789  PRKAA1; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
130585137  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
130577442  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
130578263  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
130573150  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
130584149  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
130574381  PRKAG3; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
130574293  FOXO1; forkhead box protein O1 [KO:K07201]
130572991  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
130581443  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
130576802  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
130575824  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
130575825  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
130580850  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
130583073  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
130586007  LOW QUALITY PROTEIN: regulatory-associated protein of mTOR-like [KO:K07204]
130586127  regulatory-associated protein of mTOR-like [KO:K07204]
130580972  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
130580049  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
130577843  RPS6; 40S ribosomal protein S6 [KO:K02991]
130580790  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
130573820  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
130574138  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
130576706  TSC1; hamartin isoform X1 [KO:K07206]
130576502  TSC2; tuberin isoform X1 [KO:K07207]
130573151  RHEB; GTP-binding protein Rheb [KO:K07208]
130583217  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
130580224  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
130584683  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
130575771  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
130582587  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
130583790  SOS2; son of sevenless homolog 2 [KO:K03099]
130584910  SOS1; son of sevenless homolog 1 [KO:K03099]
130576649  HRAS; GTPase HRas [KO:K02833]
130576123  KRAS; GTPase KRas isoform X1 [KO:K07827]
130578859  NRAS; GTPase NRas [KO:K07828]
130578420  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
130582944  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
130577141  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
130586756  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
130575269  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
130589267  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
130584495  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
130574211  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
130586036  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
130582009  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
130584961  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
130581387  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
130589324  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
130576378  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
130581501  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
130577953  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
130584481  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
130586376  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like [KO:K15909] [EC:3.1.3.86]
130579877  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
130584245  INPP5A; inositol polyphosphate-5-phosphatase A [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
mmea00010  Glycolysis / Gluconeogenesis
mmea00061  Fatty acid biosynthesis
mmea00500  Starch and sucrose metabolism
mmea04010  MAPK signaling pathway
mmea04070  Phosphatidylinositol signaling system
mmea04210  Apoptosis
KO pathway
ko04910   
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