KEGG   PATHWAY: mmf04910
Entry
mmf04910                    Pathway                                
Name
Insulin signaling pathway - Molossus molossus (Pallas's mastiff 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
mmf04910  Insulin signaling pathway
mmf04910

Organism
Molossus molossus (Pallas's mastiff bat) [GN:mmf]
Gene
118628933  INS; insulin [KO:K04526]
118615134  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
118625363  IRS1; insulin receptor substrate 1 [KO:K16172]
118622304  IRS2; insulin receptor substrate 2 [KO:K07187]
118636678  IRS4; insulin receptor substrate 4 [KO:K17446]
118626685  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
118642883  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118616460  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118632927  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118626944  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118617106  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118642806  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
118640620  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118619617  LOW QUALITY PROTEIN: RAC-alpha serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
118630299  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118638405  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118617870  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
118623578  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
118638432  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
118627965  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
118630486  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
118639818  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
118618813  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
118619345  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
118619653  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
118622690  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
118632319  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
118636545  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
118641943  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
118642446  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
118635603  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
118636086  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
118638404  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
118640095  calmodulin-like [KO:K02183]
118640172  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
118617946  CALM1; calmodulin-1 [KO:K02183]
118619605  calmodulin-1 [KO:K02183]
118627560  calmodulin-like [KO:K02183]
118628169  calmodulin-1-like [KO:K02183]
118636313  calmodulin-1-like [KO:K02183]
118643424  CALML6; calmodulin-like protein 6 [KO:K02183]
118630484  CALM2; calmodulin-2 [KO:K02183]
118638252  CALM3; calmodulin-3 [KO:K02183]
118631897  calmodulin-like protein 3 [KO:K02183]
118619199  PYGB; LOW QUALITY PROTEIN: glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
118628099  PYGM; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
118628411  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
118627525  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
118626166  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
118615793  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
118633068  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
118634353  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
118620111  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
118615239  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
118639408  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
118643394  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
118617164  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
118634418  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
118634971  FLOT2; flotillin-2 isoform X1 [KO:K07192]
118621376  FLOT1; flotillin-1 [KO:K07192]
118642630  SH2B2; SH2B adapter protein 2 [KO:K07193]
118632021  SORBS1; sorbin and SH3 domain-containing protein 1 [KO:K06086]
118628368  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
118617083  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
118639914  CRKL; crk-like protein [KO:K04438]
118633933  CRK; adapter molecule crk [KO:K04438]
118629452  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
118630649  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
118633835  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
118615938  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
118641324  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
118633804  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118639830  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
118633964  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
118637241  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
118644012  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
118630629  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
118632470  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
118632471  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
118619794  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
118626404  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
118641812  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
118640238  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
118637324  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
118619752  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
118624156  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
118625416  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
118622708  FOXO1; forkhead box protein O1 [KO:K07201]
118643267  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
118633799  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
118634305  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
118625387  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
118629515  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
118629672  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
118618925  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
118615675  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
118627075  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
118633821  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
118634239  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
118627654  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
118632909  40S ribosomal protein S6-like [KO:K02991]
118634553  40S ribosomal protein S6-like [KO:K02991]
118641681  40S ribosomal protein S6-like [KO:K02991]
118642003  40S ribosomal protein S6-like [KO:K02991]
118629558  RPS6; 40S ribosomal protein S6 [KO:K02991]
118622710  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
118627662  eukaryotic translation initiation factor 4E-like [KO:K03259]
118615445  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
118616276  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
118625420  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
118629416  TSC1; hamartin isoform X1 [KO:K07206]
118642250  TSC2; tuberin isoform X1 [KO:K07207]
118619958  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
118627989  BAD; bcl2-associated agonist of cell death [KO:K02158]
118637475  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118615745  SHC2; SHC-transforming protein 2 [KO:K17447]
118629877  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
118631532  SHC4; SHC-transforming protein 4 [KO:K17449]
118633806  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
118630966  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
118616724  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118643162  HRAS; GTPase HRas isoform X1 [KO:K02833]
118624619  KRAS; GTPase KRas isoform X1 [KO:K07827]
118637822  NRAS; GTPase NRas [KO:K07828]
118635666  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
118619570  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
118633343  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118628434  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
118615385  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
118640210  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
118642307  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
118627217  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
118615316  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
118636653  ELK1; LOW QUALITY PROTEIN: ETS domain-containing protein Elk-1 [KO:K04375]
118642358  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
118616246  suppressor of cytokine signaling 2-like [KO:K04695]
118624669  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
118634253  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
118616174  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
118618192  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
118626270  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
118642157  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118615122  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
118632456  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118622317  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
118627893  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
118632061  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
mmf00010  Glycolysis / Gluconeogenesis
mmf00061  Fatty acid biosynthesis
mmf00500  Starch and sucrose metabolism
mmf04010  MAPK signaling pathway
mmf04070  Phosphatidylinositol signaling system
mmf04210  Apoptosis
KO pathway
ko04910   
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