KEGG   PATHWAY: pmaj04910
Entry
pmaj04910                   Pathway                                
Name
Insulin signaling pathway - Parus major (Great Tit)
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
pmaj04910  Insulin signaling pathway
pmaj04910

Organism
Parus major (Great Tit) [GN:pmaj]
Gene
107205419  INS; insulin [KO:K04526]
107215564  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
107208936  IRS1; insulin receptor substrate 1 [KO:K16172]
107203717  IRS4; insulin receptor substrate 4 [KO:K07187]
107208306  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
107215603  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
107208273  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
107216262  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
107213667  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
107208827  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
107208852  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
107211032  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
107201442  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
107205807  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
107205227  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
107205059  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
107201313  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
107211824  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
107205266  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
107205208  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
107209886  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
107213265  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
107203617  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
107207109  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
107199605  protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
107212749  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
107203763  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
107208180  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
107209813  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
107204237  calmodulin, striated muscle [KO:K02183]
107201314  CALM2; calmodulin-2 isoform X1 [KO:K02183]
107205523  CALM1; calmodulin-1 [KO:K02183]
107209103  CALML4; calmodulin-like protein 4 [KO:K02183]
107202033  glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
107206328  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
107205883  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
107208204  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
107204309  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
107210329  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
107211260  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
107212581  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
107213615  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
107208929  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
107212937  FLOT2; flotillin-2 isoform X1 [KO:K07192]
107213014  SH2B2; SH2B adapter protein 2 [KO:K07193]
107206628  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X40 [KO:K06086]
107214346  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
107208416  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
107212927  CRK; adapter molecule crk isoform X3 [KO:K04438]
107211597  CRKL; crk-like protein [KO:K04438]
107211975  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
107201660  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
107212519  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
107211194  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
107212824  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
107211484  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
107212310  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
107206912  hexokinase HKDC1-like isoform X1 [KO:K00844] [EC:2.7.1.1]
107213868  LOW QUALITY PROTEIN: hexokinase-2 [KO:K00844] [EC:2.7.1.1]
107210802  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
107206960  hexokinase-1 [KO:K00844] [EC:2.7.1.1]
107213875  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
107216196  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
107208272  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
107208034  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
107211650  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
107198595  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
107216388  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
107207521  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
107210372  FOXO1; forkhead box protein O1 [KO:K07201]
107203280  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
107207353  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
107215190  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
107199063  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
107198219  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
107198220  FBP2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
107213302  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
107213730  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
107212280  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
107206395  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
107212783  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
107216011  RPS6; 40S ribosomal protein S6 [KO:K02991]
107213862  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 isoform X1 [KO:K07205]
107203296  EIF4E; eukaryotic translation initiation factor 4E isoform X3 [KO:K03259]
107210803  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
107208705  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
107212076  TSC1; hamartin isoform X1 [KO:K07206]
107211281  TSC2; tuberin isoform X2 [KO:K07207]
107200479  RHEB; GTP-binding protein Rheb [KO:K07208]
107214540  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
107215430  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
107216331  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
107209575  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
107212507  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
107206011  SOS2; son of sevenless homolog 2 [KO:K03099]
107201824  SOS1; son of sevenless homolog 1 isoform X2 [KO:K03099]
107205559  HRAS; GTPase HRas [KO:K02833]
107204562  KRAS; GTPase KRas isoform X1 [KO:K07827]
107214761  NRAS; GTPase NRas [KO:K07828]
107204658  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
107210130  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
107209483  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
107215477  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
107211727  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
107215565  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
107208397  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
107211147  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
107204420  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
107212347  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
107206463  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
107213436  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
107208126  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
107210724  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
107203419  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
107206805  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
107213912  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
107203647  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like [KO:K15909] [EC:3.1.3.86]
107212504  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X2 [KO:K15909] [EC:3.1.3.86]
107206908  INPP5A; inositol polyphosphate-5-phosphatase A 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
pmaj00010  Glycolysis / Gluconeogenesis
pmaj00061  Fatty acid biosynthesis
pmaj00500  Starch and sucrose metabolism
pmaj04010  MAPK signaling pathway
pmaj04070  Phosphatidylinositol signaling system
pmaj04210  Apoptosis
KO pathway
ko04910   
LinkDB

DBGET integrated database retrieval system