KEGG   PATHWAY: oga04910
Entry
oga04910                    Pathway                                
Name
Insulin signaling pathway - Otolemur garnettii (small-eared galago)
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
oga04910  Insulin signaling pathway
oga04910

Organism
Otolemur garnettii (small-eared galago) [GN:oga]
Gene
100958310  INS; insulin isoform X1 [KO:K04526]
100962237  INSR; insulin receptor isoform X3 [KO:K04527] [EC:2.7.10.1]
100958778  IRS1; insulin receptor substrate 1 [KO:K16172]
100951299  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
100953605  IRS4; insulin receptor substrate 4 isoform X2 [KO:K17446]
100956838  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
100952580  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
100949858  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100947138  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100953367  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100954109  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100950210  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
100959825  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100955276  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100945977  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100952751  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
100956758  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
100949141  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100941909  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100960152  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100945379  serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269] [EC:3.1.3.16]
100955191  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100940860  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
100949665  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
100966727  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100944077  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
100951610  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
100942099  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
100953265  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X2 [KO:K00871] [EC:2.7.11.19]
100951651  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
100956924  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
100952734  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
100952803  calmodulin-like [KO:K02183]
100956147  calmodulin-like [KO:K02183]
105887316  CALML6; calmodulin-like protein 6 [KO:K02183]
100942721  calmodulin-like [KO:K02183]
100941613  CALM3; calmodulin-3 [KO:K02183]
100964319  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
100946498  CALM2; calmodulin-2 [KO:K02183]
100966114  CALML5; calmodulin-like protein 5 [KO:K02183]
100948288  CALM1; calmodulin-1 [KO:K02183]
100943479  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100949519  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
100966783  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100961357  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
100964083  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100966533  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100960086  LOW QUALITY PROTEIN: cAMP-dependent protein kinase type II-alpha regulatory subunit-like [KO:K04739]
100949395  PRKAR2A; LOW QUALITY PROTEIN: cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
100950156  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
100962757  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
100944321  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
100952035  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
100965310  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100954111  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
100945996  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100947689  FLOT2; flotillin-2 isoform X1 [KO:K07192]
100951662  FLOT1; flotillin-1 isoform X1 [KO:K07192]
100964578  SH2B2; LOW QUALITY PROTEIN: SH2B adapter protein 2 [KO:K07193]
100966763  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X6 [KO:K06086]
100958294  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
100942227  CBLB; E3 ubiquitin-protein ligase CBL-B [KO:K22517] [EC:2.3.2.27]
100958636  CRK; adapter molecule crk isoform X1 [KO:K04438]
100951208  CRKL; crk-like protein [KO:K04438]
100965849  RAPGEF1; rap guanine nucleotide exchange factor 1 [KO:K06277]
100944391  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
100941015  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
100946755  TRIP10; cdc42-interacting protein 4 isoform X2 [KO:K07196]
100955236  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
100951894  ACACA; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100959432  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100947008  FASN; fatty acid synthase isoform X1 [KO:K00665] [EC:2.3.1.85]
100955995  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
100947200  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
105886409  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
100959804  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100963430  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
100954843  GCK; glucokinase isoform X2 [KO:K12407] [EC:2.7.1.2]
100948837  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
100947892  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100943975  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100963213  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
100941359  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100944531  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
100947945  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100960421  FOXO1; forkhead box protein O1 [KO:K07201]
100965953  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X4 [KO:K07202]
100941852  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100950588  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100966484  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
100963037  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
100963356  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
100941836  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100963401  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100957753  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100955618  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
100945805  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100940650  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X5 [KO:K04688] [EC:2.7.11.1]
100960641  RPS6; 40S ribosomal protein S6 [KO:K02991]
100963859  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100958672  EIF4E2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
100956985  eukaryotic translation initiation factor 4E [KO:K03259]
100963018  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
100966830  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
100954949  TSC1; hamartin isoform X2 [KO:K07206]
100956811  TSC2; tuberin isoform X3 [KO:K07207]
100950216  RHEB; GTP-binding protein Rheb [KO:K07208]
100962306  BAD; bcl2-associated agonist of cell death [KO:K02158]
100966694  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100957623  SHC2; SHC-transforming protein 2 [KO:K17447]
100952749  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
100945538  SHC4; SHC-transforming protein 4 [KO:K17449]
100948701  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100958517  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100943020  SOS2; son of sevenless homolog 2 [KO:K03099]
100951644  HRAS; GTPase HRas isoform X1 [KO:K02833]
100953050  KRAS; GTPase KRas isoform X3 [KO:K07827]
100949583  NRAS; GTPase NRas isoform X1 [KO:K07828]
100947929  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
100955336  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100941062  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100959926  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100956072  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X2 [KO:K04369] [EC:2.7.12.2]
100951533  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100957343  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100955096  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
100942287  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X2 [KO:K04372] [EC:2.7.11.1]
100949181  ELK1; ETS domain-containing protein Elk-1 isoform X2 [KO:K04375]
100947728  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
100942876  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100960974  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100957947  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
100952815  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
100958136  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X4 [KO:K05695] [EC:3.1.3.48]
100957169  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100967053  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100960275  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100946157  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100943689  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
100941367  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [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
oga00010  Glycolysis / Gluconeogenesis
oga00061  Fatty acid biosynthesis
oga00500  Starch and sucrose metabolism
oga04010  MAPK signaling pathway
oga04070  Phosphatidylinositol signaling system
oga04210  Apoptosis
KO pathway
ko04910   
LinkDB

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