KEGG   PATHWAY: cata04910
Entry
cata04910                   Pathway                                
Name
Insulin signaling pathway - Cygnus atratus (black swan)
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
cata04910  Insulin signaling pathway
cata04910

Organism
Cygnus atratus (black swan) [GN:cata]
Gene
118244761  INS; insulin [KO:K04526]
118258731  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
118247238  IRS1; insulin receptor substrate 1 [KO:K16172]
118257481  IRS2; insulin receptor substrate 2 [KO:K07187]
118245459  IRS4; insulin receptor substrate 4 [KO:K07187]
118243598  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
118251494  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
118258749  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118247018  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
118253156  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
118253338  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
118256396  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
118261257  AKT2; LOW QUALITY PROTEIN: RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118250209  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118256722  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118244932  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
118245134  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
118256031  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
118244447  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
118257540  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
118247471  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
118248634  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
118248820  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
118255993  protein phosphatase 1 regulatory subunit 3C-B-like isoform X1 [KO:K07189]
118246265  protein phosphatase 1 regulatory subunit 3E-like [KO:K07189]
118246756  PPP1R3A; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3A [KO:K07189]
118254204  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
118245399  PHKA1; LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
118245707  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
118246562  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
118259682  CALML4; calmodulin-like protein 4 [KO:K02183]
118261160  calmodulin-like [KO:K02183]
118256005  CALM2; calmodulin-2 isoform X1 [KO:K02183]
118244234  CALM1; calmodulin-1 [KO:K02183]
118258059  calmodulin, striated muscle [KO:K02183]
118253331  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
118250234  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
118249770  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B isoform X1 [KO:K13296] [EC:3.1.4.17]
118243752  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
118253870  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
118248249  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
118249099  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
118249473  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
118253440  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
118253155  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
118261231  FLOT1; flotillin-1 isoform X1 [KO:K07192]
118255093  FLOT2; flotillin-2 isoform X5 [KO:K07192]
118254182  SH2B2; SH2B adapter protein 2 [KO:K07193]
118255570  SORBS1; LOW QUALITY PROTEIN: sorbin and SH3 domain-containing protein 1 [KO:K06086]
118252523  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
118244975  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
118254099  CRK; adapter molecule crk isoform X1 [KO:K04438]
118252963  CRKL; crk-like protein [KO:K04438]
118252179  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
118257322  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
118253937  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
118256409  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
118255177  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118257611  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118259221  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
118259365  hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
118254417  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
118243824  hexokinase HKDC1-like isoform X1 [KO:K00844] [EC:2.7.1.1]
118246683  hexokinase-1 [KO:K00844] [EC:2.7.1.1]
118260953  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
118243521  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
118257770  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
118243352  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
118252942  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
118261344  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
118251785  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X2 [KO:K07200]
118252618  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
118245930  FOXO1; forkhead box protein O1 [KO:K07201]
118251103  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
118261712  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
118259113  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X2 [KO:K01084] [EC:3.1.3.9]
118257379  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
118257380  LOW QUALITY PROTEIN: fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
118248825  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
118253301  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
118259298  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
118255011  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X2 [KO:K04688] [EC:2.7.11.1]
118244482  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
118253816  RPS6; 40S ribosomal protein S6 [KO:K02991]
118256105  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
118247121  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
118259308  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
118254494  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
118252095  TSC1; hamartin isoform X1 [KO:K07206]
118256451  TSC2; tuberin isoform X1 [KO:K07207]
118251786  RHEB; GTP-binding protein Rheb [KO:K07208]
118258448  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118260038  SHC2; SHC-transforming protein 2 [KO:K17447]
118259571  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
118251605  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
118253962  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
118250305  SOS2; son of sevenless homolog 2 [KO:K03099]
118251111  SOS1; son of sevenless homolog 1 [KO:K03099]
118250718  HRAS; GTPase HRas [KO:K02833]
118245139  KRAS; GTPase KRas isoform X1 [KO:K07827]
118255298  NRAS; GTPase NRas [KO:K07828]
118259202  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
118253692  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118252022  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
118258785  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
118252877  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
118259839  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
118243646  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
118249179  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
118250504  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
118259262  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
118250253  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
118248786  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
118243260  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
118254865  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
118248962  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118243928  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118256066  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
118261081  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
118245362  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like isoform X1 [KO:K15909] [EC:3.1.3.86]
118248541  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
cata00010  Glycolysis / Gluconeogenesis
cata00061  Fatty acid biosynthesis
cata00500  Starch and sucrose metabolism
cata04010  MAPK signaling pathway
cata04070  Phosphatidylinositol signaling system
cata04210  Apoptosis
KO pathway
ko04910   
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