KEGG   PATHWAY: apla04910
Entry
apla04910                   Pathway                                
Name
Insulin signaling pathway - Anas platyrhynchos (mallard)
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
apla04910  Insulin signaling pathway
apla04910

Organism
Anas platyrhynchos (mallard) [GN:apla]
Gene
101789385  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
101789545  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101789789  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
101789891  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
101790148  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
101790182  CALM1; calmodulin [KO:K02183]
101790247  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
101790255  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
101790963  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
101791037  MAP2K1; LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101791054  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
101791200  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101791756  [KO:K07189]
101791792  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
101791856  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X3 [KO:K04345] [EC:2.7.11.11]
101791867  G6PC1; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
101792705  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
101792883  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101793068  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
101793538  KRAS; GTPase KRas isoform X1 [KO:K07827]
101793594  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101793637  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
101793649  HRAS; GTPase HRas [KO:K02833]
101793747  FLOT2; flotillin-2 isoform X1 [KO:K07192]
101793961  CRK; adapter molecule crk isoform X1 [KO:K04438]
101793994  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
101794107  [KO:K00844] [EC:2.7.1.1]
101794281  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
101794283  [KO:K00844] [EC:2.7.1.1]
101794322  PHKB; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
101794380  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
101794427  INS; insulin [KO:K04526]
101794448  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
101794843  SH2B2; LOW QUALITY PROTEIN: SH2B adapter protein 2 [KO:K07193]
101795011  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
101795447  FOXO1; forkhead box protein O1 [KO:K07201]
101795633  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101795759  [KO:K02649]
101795803  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
101796035  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X2 [KO:K07189]
101796183  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101796349  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
101796594  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
101796950  IRS1; LOW QUALITY PROTEIN: insulin receptor substrate 1 [KO:K16172]
101796973  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
101796993  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
101797165  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
101797178  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
101797278  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
101797458  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
101797571  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
101798010  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
101798259  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
101798286  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101798545  TSC1; hamartin isoform X1 [KO:K07206]
101798783  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
101799011  MAPK9; mitogen-activated protein kinase 9 isoform X5 [KO:K04440] [EC:2.7.11.24]
101799051  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
101799561  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
101799716  CALM2; calmodulin-2 [KO:K02183]
101799717  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
101800303  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X37 [KO:K06086]
101800319  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101800458  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101800491  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
101800900  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101800988  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
101801136  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
101801184  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
101801250  RPS6; 40S ribosomal protein S6 [KO:K02991]
101801370  PTPN1; LOW QUALITY PROTEIN: tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
101801595  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
101801905  [KO:K07187]
101801940  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101802112  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
101802245  SOS1; son of sevenless homolog 1 [KO:K03099]
101802486  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101802796  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101802849  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
101802994  [KO:K03841] [EC:3.1.3.11]
101803461  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101803710  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
101803921  RHEB; GTP-binding protein Rheb isoform X2 [KO:K07208]
101803934  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X3 [KO:K07199]
101803969  SHC2; SHC-transforming protein 2 [KO:K17447]
101804204  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [KO:K01106] [EC:3.1.3.56]
101804231  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
101804261  [KO:K03841] [EC:3.1.3.11]
101804276  CALML4; calmodulin-like protein 4 [KO:K02183]
101804354  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
101804390  [KO:K00688] [EC:2.4.1.1]
101804556  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101804570  CRKL; crk-like protein [KO:K04438]
101804628  SOS2; son of sevenless homolog 2 [KO:K03099]
101804723  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
101804733  NRAS; LOW QUALITY PROTEIN: GTPase NRas [KO:K07828]
101804966  TSC2; tuberin isoform X5 [KO:K07207]
101805035  HK3; LOW QUALITY PROTEIN: hexokinase-3 [KO:K00844] [EC:2.7.1.1]
101805317  [KO:K02183]
101805480  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
106014314  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
113844108  PRKAG3; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
113844956  [KO:K07189]
113845251  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
119713154  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
119713155  RPTOR; LOW QUALITY PROTEIN: regulatory-associated protein of mTOR [KO:K07204]
119713467  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
119714201  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
119714791  FLOT1; flotillin-1 [KO:K07192]
119714987  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
119715227  GCK; LOW QUALITY PROTEIN: hexokinase-4 [KO:K12407] [EC:2.7.1.2]
119715285  PRKAG1; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
119717128  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
119717225  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
119717868  [KO:K15909] [EC:3.1.3.86]
119718363  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
119718491  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
119718533  ACACB; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
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
apla00010  Glycolysis / Gluconeogenesis
apla00061  Fatty acid biosynthesis
apla00500  Starch and sucrose metabolism
apla04010  MAPK signaling pathway
apla04070  Phosphatidylinositol signaling system
apla04210  Apoptosis
KO pathway
ko04910   

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