KEGG   PATHWAY: pale04910
Entry
pale04910                   Pathway                                
Name
Insulin signaling pathway - Pteropus alecto (black 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
pale04910  Insulin signaling pathway
pale04910

Organism
Pteropus alecto (black flying fox) [GN:pale]
Gene
102881117  insulin [KO:K04526]
102879346  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
102891583  IRS1; insulin receptor substrate 1 [KO:K16172]
102898575  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
102895007  IRS4; insulin receptor substrate 4 [KO:K17446]
102879163  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102891637  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X3 [KO:K02649]
102879453  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102889227  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102880320  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102889576  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102896950  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102885144  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102879337  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102898305  AKT2; LOW QUALITY PROTEIN: RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102882441  GSK3B; glycogen synthase kinase-3 beta isoform X4 [KO:K03083] [EC:2.7.11.26]
102890809  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
102884634  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
102892254  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
102881448  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102887827  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102897087  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
102891010  PPP1R3D; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102891839  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
102890505  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
102882220  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
102893365  PPP1R3F; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3F [KO:K17453]
102879938  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
102882222  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
102879995  PHKB; LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit beta [KO:K07190]
102882713  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
102892742  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
102894226  CALM2; calmodulin-2 isoform X1 [KO:K02183]
102897273  CALM3; calmodulin-3 [KO:K02183]
102886058  CALM1; calmodulin-1 [KO:K02183]
102884196  CALML6; calmodulin-like protein 6 [KO:K02183]
102891673  calmodulin-like [KO:K02183]
102893109  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
102881744  calmodulin-like [KO:K02183]
102887527  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
102897270  PYGM; glycogen phosphorylase, muscle form isoform X2 [KO:K00688] [EC:2.4.1.1]
102878850  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
102894289  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
102886679  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102877853  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102884719  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
102885074  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
102890070  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
102889858  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
102892135  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
102881706  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
102881931  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
102897887  FLOT2; flotillin-2 isoform X1 [KO:K07192]
102882311  FLOT1; flotillin-1 isoform X2 [KO:K07192]
102898524  SH2B2; SH2B adapter protein 2 [KO:K07193]
102891433  SORBS1; LOW QUALITY PROTEIN: sorbin and SH3 domain-containing protein 1 [KO:K06086]
102895335  CBL; LOW QUALITY PROTEIN: E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
102890283  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
102898080  CRKL; crk-like protein [KO:K04438]
102885553  CRK; adapter molecule crk isoform X1 [KO:K04438]
102882490  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
102896350  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
102894067  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
102882845  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
102882131  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
102895052  ACACA; acetyl-CoA carboxylase 1 isoform X3 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102887451  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102887167  FASN; LOW QUALITY PROTEIN: fatty acid synthase [KO:K00665] [EC:2.3.1.85]
102888780  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
102892478  HK2; LOW QUALITY PROTEIN: hexokinase-2 [KO:K00844] [EC:2.7.1.1]
102878115  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
102898766  HK1; LOW QUALITY PROTEIN: hexokinase-1 [KO:K00844] [EC:2.7.1.1]
102894665  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
102884319  GCK; LOW QUALITY PROTEIN: glucokinase [KO:K12407] [EC:2.7.1.2]
102884524  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102886520  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102886980  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
102887949  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102898038  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
102882613  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X3 [KO:K07200]
102887347  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
102892244  FOXO1; forkhead box protein O1 [KO:K07201]
102879270  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
102887492  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102896886  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102898137  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
102882419  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
102882663  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
102888528  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
102897596  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
102885092  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102885334  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
102891214  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
102889369  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
102891633  RPS6; 40S ribosomal protein S6 [KO:K02991]
102881655  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
102898578  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
102894970  EIF4E2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
102898723  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
102878835  TSC1; LOW QUALITY PROTEIN: hamartin [KO:K07206]
102898762  TSC2; tuberin isoform X11 [KO:K07207]
102889101  RHEB; GTP-binding protein Rheb [KO:K07208]
102877892  BAD; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
102894443  SHC1; LOW QUALITY PROTEIN: SHC-transforming protein 1 [KO:K06279]
102885958  SHC2; SHC-transforming protein 2 [KO:K17447]
102879956  SHC3; SHC-transforming protein 3 [KO:K17448]
102888926  SHC4; SHC-transforming protein 4 [KO:K17449]
102878822  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
102882462  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102889597  SOS2; son of sevenless homolog 2 [KO:K03099]
102896270  HRAS; GTPase HRas isoform X3 [KO:K02833]
102895590  KRAS; GTPase KRas isoform X1 [KO:K07827]
102885950  NRAS; GTPase NRas isoform X2 [KO:K07828]
102877877  ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:2.7.11.1]
102878393  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
102893439  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102897122  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
102879034  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102895390  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102885749  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102898528  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
102883519  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
102878877  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
102878735  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
102889529  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
102887834  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102879275  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
102896636  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
102882304  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X2 [KO:K05695] [EC:3.1.3.48]
102885064  MAPK10; mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
102890689  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102892777  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102893261  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
102890098  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
102886411  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
pale00010  Glycolysis / Gluconeogenesis
pale00061  Fatty acid biosynthesis
pale00500  Starch and sucrose metabolism
pale04010  MAPK signaling pathway
pale04070  Phosphatidylinositol signaling system
pale04210  Apoptosis
KO pathway
ko04910   
LinkDB

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