KEGG   PATHWAY: pgig04910
Entry
pgig04910                   Pathway                                
Name
Insulin signaling pathway - Pteropus vampyrus (Indian flying fox)
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
pgig04910  Insulin signaling pathway
pgig04910

Organism
Pteropus vampyrus (Indian flying fox) [GN:pgig]
Gene
120581223  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [KO:K01106] [EC:3.1.3.56]
120582132  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
120582323  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
120582783  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
120583269  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
120583719  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
120583890  FOXO1; forkhead box protein O1 [KO:K07201]
120584612  INS; insulin [KO:K04526]
120584662  HRAS; GTPase HRas isoform X1 [KO:K02833]
120584753  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
120584763  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
120585069  NRAS; GTPase NRas isoform X1 [KO:K07828]
120585136  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
120585413  PHKA1; LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
120585826  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
120585845  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
120586161  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
120586669  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
120586970  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
120587065  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
120587666  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
120588339  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
120588349  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
120589065  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
120589204  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
120589513  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
120589556  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
120589639  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
120589870  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
120590298  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
120591512  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
120591566  SH2B2; SH2B adapter protein 2 [KO:K07193]
120591810  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
120592122  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
120592211  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
120593377  FLOT1; flotillin-1 isoform X1 [KO:K07192]
120593612  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
120594118  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
120594298  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
120594630  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
120595025  [KO:K02991]
120595621  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
120595665  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
120595669  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
120596847  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
120596984  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
120597107  IRS1; insulin receptor substrate 1 [KO:K16172]
120597214  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
120598144  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
120599285  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
120600032  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
120600162  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
120600169  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
120600272  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
120600316  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
120600334  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
120600645  BAD; bcl2-associated agonist of cell death [KO:K02158]
120600705  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
120601110  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
120601203  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
120601454  RHEB; GTP-binding protein Rheb [KO:K07208]
120601493  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
120601871  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
120602724  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
120602738  TSC1; hamartin isoform X1 [KO:K07206]
120603240  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
120603810  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
120603862  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
120603895  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
120604299  [KO:K02991]
120604376  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
120604438  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
120604448  SOS2; son of sevenless homolog 2 [KO:K03099]
120604475  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
120604492  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
120605338  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
120605522  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
120605533  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
120605611  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
120605700  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
120605971  [KO:K07196]
120606549  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
120606777  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
120606834  CRKL; crk-like protein [KO:K04438]
120606851  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
120606948  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
120607291  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
120608247  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
120608272  RPS6; 40S ribosomal protein S6 [KO:K02991]
120608500  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
120608993  [KO:K02183]
120609272  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
120609316  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
120609335  [KO:K04438]
120609468  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
120609469  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
120609636  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
120611062  G6PC1; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
120613959  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
120614038  [KO:K04438]
120614115  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
120615108  [KO:K02991]
120615382  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
120615454  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
120615834  [KO:K03259]
120615896  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
120616096  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
120616378  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
120616548  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
120616551  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
120616614  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
120616910  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
120616911  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
120617236  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
120617886  CALM3; calmodulin-3 [KO:K02183]
120618205  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
120618351  KRAS; GTPase KRas isoform X1 [KO:K07827]
120618372  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
120618485  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
120619079  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
120619283  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
120619605  CALM1; calmodulin-1 [KO:K02183]
120620078  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
120620121  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
120620206  [KO:K02649]
120620251  TSC2; tuberin isoform X1 [KO:K07207]
120620273  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
120620328  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
120620390  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
120620825  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
120620973  FLOT2; flotillin-2 isoform X1 [KO:K07192]
120621033  CRK; adapter molecule crk isoform X1 [KO:K04438]
120621151  ACACA; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
120621476  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
120621675  CALM2; calmodulin-2 isoform X1 [KO:K02183]
120621686  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
120621730  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
120621751  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
120621819  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
120622672  SHC4; SHC-transforming protein 4 [KO:K17449]
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
pgig00010  Glycolysis / Gluconeogenesis
pgig00061  Fatty acid biosynthesis
pgig00500  Starch and sucrose metabolism
pgig04010  MAPK signaling pathway
pgig04070  Phosphatidylinositol signaling system
pgig04210  Apoptosis
KO pathway
ko04910   

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