KEGG   PATHWAY: phas04910
Entry
phas04910                   Pathway                                
Name
Insulin signaling pathway - Phyllostomus hastatus (greater spear-nosed bat)
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
phas04910  Insulin signaling pathway
phas04910

Organism
Phyllostomus hastatus (greater spear-nosed bat) [GN:phas]
Gene
123807354  INS; insulin isoform X1 [KO:K04526]
123811181  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
123828676  IRS1; insulin receptor substrate 1 [KO:K16172]
123807405  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
123805137  IRS4; insulin receptor substrate 4 [KO:K17446]
123828291  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
123824527  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
123832298  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
123826750  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
123830565  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
123831922  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
123807097  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
123808608  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
123823743  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
123832297  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
123827255  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
123812688  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
123830251  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
123821109  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
123829523  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
123822478  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
123820438  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
123828951  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
123807527  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
123814748  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
123824637  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
123832822  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
123806334  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
123825658  phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
123819032  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
123805860  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
123829874  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
123811737  CALM2; calmodulin-2 [KO:K02183]
123821009  calmodulin-1-like [KO:K02183]
123808002  CALM1; calmodulin-1 [KO:K02183]
123808036  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
123823025  CALM3; calmodulin-3 [KO:K02183]
123831226  CALML3; calmodulin-like protein 3 [KO:K02183]
123831240  calmodulin-like [KO:K02183]
123831845  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
123829276  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
123808196  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
123810006  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
123828245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
123816440  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
123811943  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
123830664  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
123809594  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
123817105  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
123818235  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
123831995  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
123827105  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
123809243  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
123817045  FLOT2; flotillin-2 isoform X1 [KO:K07192]
123810476  FLOT1; flotillin-1 isoform X1 [KO:K07192]
123806264  SH2B2; SH2B adapter protein 2 [KO:K07193]
123828731  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
123818694  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
123827009  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
123806597  CRKL; crk-like protein isoform X1 [KO:K04438]
123817321  CRK; adapter molecule crk isoform X1 [KO:K04438]
123823357  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
123812029  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
123816981  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
123813811  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
123809238  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
123816701  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
123822289  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
123816716  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
123804602  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
123811416  HK2; LOW QUALITY PROTEIN: hexokinase-2 [KO:K00844] [EC:2.7.1.1]
123820909  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
123820910  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
123810029  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
123811692  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
123830412  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
123824594  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
123804388  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
123820791  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
123813127  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
123829421  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
123817947  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
123818794  FOXO1; forkhead box protein O1 [KO:K07201]
123815639  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
123821322  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
123817295  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
123817418  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
123819456  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
123819464  FBP2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
123820444  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
123815008  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
123831556  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
123816937  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
123829298  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
123817599  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
123819683  RPS6; 40S ribosomal protein S6 [KO:K02991]
123805431  40S ribosomal protein S6-like [KO:K02991]
123820789  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
123828526  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
123829778  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
123808751  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
123807542  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
123812804  eukaryotic translation initiation factor 4E-like [KO:K03259]
123813039  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
123806860  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
123823219  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
123823356  TSC1; hamartin isoform X1 [KO:K07206]
123807207  TSC2; tuberin isoform X1 [KO:K07207]
123818003  RHEB; GTP-binding protein Rheb [KO:K07208]
123829336  BAD; bcl2-associated agonist of cell death [KO:K02158]
123804815  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
123813838  SHC2; SHC-transforming protein 2 [KO:K17447]
123815569  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
123808639  SHC4; SHC-transforming protein 4 [KO:K17449]
123817350  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
123811120  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
123807983  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
123807317  HRAS; GTPase HRas isoform X1 [KO:K02833]
123812406  KRAS; GTPase KRas isoform X1 [KO:K07827]
123804414  NRAS; GTPase NRas [KO:K07828]
123832643  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
123829653  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
123814364  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
123808110  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
123813640  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
123806569  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
123825523  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
123813990  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
123832050  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
123832645  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
123806422  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
123805849  suppressor of cytokine signaling 2-like [KO:K04695]
123813545  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
123816752  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
123808769  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
123814833  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
123832233  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
123820887  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
123806902  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
123807193  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
123807522  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
123805434  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
123828723  INPP5A; inositol polyphosphate-5-phosphatase A 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
phas00010  Glycolysis / Gluconeogenesis
phas00061  Fatty acid biosynthesis
phas00500  Starch and sucrose metabolism
phas04010  MAPK signaling pathway
phas04070  Phosphatidylinositol signaling system
phas04210  Apoptosis
KO pathway
ko04910   
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