KEGG   PATHWAY: pvp04910
Entry
pvp04910                    Pathway                                
Name
Insulin signaling pathway - Pteropus vampyrus (large 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
pvp04910  Insulin signaling pathway
pvp04910

Organism
Pteropus vampyrus (large flying fox) [GN:pvp]
Gene
105307438  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
105294748  IRS1; insulin receptor substrate 1 [KO:K16172]
105301327  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
105301581  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
105296605  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105297140  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105299371  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
105307215  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105307575  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105308956  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
105303144  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105303899  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105300159  RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
105298702  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105301304  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
105306545  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
105301759  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
105289220  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105299132  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
105309924  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
105299821  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
105293089  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
105300291  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
105300540  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
105311258  PPP1R3D; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3D [KO:K07189]
105309052  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
105296734  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
105304523  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
105307759  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
105294024  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
105301201  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
105297322  CALM3; calmodulin-3 [KO:K02183]
105290127  CALM1; calmodulin-1 [KO:K02183]
105299180  calmodulin [KO:K02183]
105292913  CALM2; calmodulin-2 isoform X1 [KO:K02183]
105309689  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
105303606  CALML6; calmodulin-like protein 6 [KO:K02183]
105304070  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
105310228  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
105297994  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
105301483  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
105289063  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105308501  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
105294592  cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
105297745  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
105300331  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
105302366  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
105307364  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
105303610  PRKCZ; LOW QUALITY PROTEIN: protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
105305616  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
105291195  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
105291903  FLOT2; flotillin-2 isoform X1 [KO:K07192]
105308136  FLOT1; flotillin-1 isoform X1 [KO:K07192]
105299711  SH2B2; SH2B adapter protein 2 [KO:K07193]
105301358  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
105308867  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
105309876  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
105289311  CRKL; crk-like protein [KO:K04438]
105291866  CRK; adapter molecule crk isoform X1 [KO:K04438]
105298681  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
105292920  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
105293428  EXOC7; exocyst complex component 7 [KO:K07195]
105301087  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
105291333  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
105304993  ACACA; acetyl-CoA carboxylase 1 isoform X3 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
105303961  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
105301128  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
105296362  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
105290772  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
105300108  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
105300133  hexokinase-1 [KO:K00844] [EC:2.7.1.1]
105293519  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
105308746  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
105299096  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
105298997  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
105289266  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105297801  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
105297531  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X3 [KO:K07200]
105291053  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X2 [KO:K07200]
105303778  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
105298901  FOXO1; forkhead box protein O1 [KO:K07201]
105295511  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
105290741  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
105306265  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
105303498  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
105306919  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
105306920  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
105298776  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
105310334  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
105294429  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
105301186  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
105306550  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
105302100  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105295596  RPS6; 40S ribosomal protein S6 [KO:K02991]
105300185  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
105289536  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
105305994  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
105293632  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
105298655  TSC1; hamartin isoform X1 [KO:K07206]
105303335  TSC2; LOW QUALITY PROTEIN: tuberin [KO:K07207]
105303777  RHEB; GTP-binding protein Rheb [KO:K07208]
105297848  BAD; bcl2-associated agonist of cell death [KO:K02158]
105296379  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
105302278  SHC2; SHC-transforming protein 2 [KO:K17447]
105300265  SHC3; SHC-transforming protein 3 [KO:K17448]
105288811  SHC4; SHC-transforming protein 4 [KO:K17449]
105293353  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
105292949  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105309535  SOS2; son of sevenless homolog 2 [KO:K03099]
105305933  HRAS; GTPase HRas isoform X1 [KO:K02833]
105294059  KRAS; GTPase KRas isoform X2 [KO:K07827]
105296550  NRAS; GTPase NRas isoform X1 [KO:K07828]
105305459  ARAF; serine/threonine-protein kinase A-Raf isoform X8 [KO:K08845] [EC:2.7.11.1]
105291659  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
105299021  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105309827  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
105306744  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105289326  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
105304566  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
105297153  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
105300455  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
105305461  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
105290926  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
105293246  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
105293447  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
105309162  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
105296070  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
105297093  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X4 [KO:K05695] [EC:3.1.3.48]
105288933  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105289628  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
105299978  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105301022  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
105303690  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
105300399  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [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
pvp00010  Glycolysis / Gluconeogenesis
pvp00061  Fatty acid biosynthesis
pvp00500  Starch and sucrose metabolism
pvp04010  MAPK signaling pathway
pvp04070  Phosphatidylinositol signaling system
pvp04210  Apoptosis
KO pathway
ko04910   
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