KEGG   PATHWAY: mlf04910
Entry
mlf04910                    Pathway                                
Name
Insulin signaling pathway - Myotis lucifugus (little brown 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
mlf04910  Insulin signaling pathway
mlf04910

Organism
Myotis lucifugus (little brown bat) [GN:mlf]
Gene
102430737  INS; insulin [KO:K04526]
102437355  INSR; LOW QUALITY PROTEIN: insulin receptor [KO:K04527] [EC:2.7.10.1]
102442509  IRS1; insulin receptor substrate 1 [KO:K16172]
102429074  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
102418401  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
102427890  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102441522  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102429230  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102426106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102419324  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102422649  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102441064  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102433534  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102431196  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102443221  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102439923  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102428794  GSK3B; glycogen synthase kinase-3 beta isoform X13 [KO:K03083] [EC:2.7.11.26]
102422372  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
102439331  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
102437203  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102436383  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102429857  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X2 [KO:K06269] [EC:3.1.3.16]
102417633  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102423504  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
102426781  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
102420654  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
102424879  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102434943  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
102423171  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
102441572  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
102431515  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
102437379  PHKA2; LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
102431229  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
102430787  CALM2; calmodulin-2 isoform X1 [KO:K02183]
102417912  calmodulin-A-like isoform X1 [KO:K02183]
102419493  calmodulin-like protein 3 [KO:K02183]
102419808  calmodulin-like protein 5 [KO:K02183]
102426645  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
102434863  CALM1; calmodulin-1 [KO:K02183]
102440407  calmodulin-like [KO:K02183]
102443136  calmodulin-like [KO:K02183]
102433488  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
102440006  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
102439611  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
102431150  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
102437773  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102417960  PRKACA; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102439617  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
102439385  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
102434825  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
102426455  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
102431883  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
102419367  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
102433783  FLOT2; LOW QUALITY PROTEIN: flotillin-2 [KO:K07192]
102441574  FLOT1; flotillin-1 [KO:K07192]
102428884  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
102438405  SORBS1; sorbin and SH3 domain-containing protein 1 [KO:K06086]
102420957  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
102432845  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
102440736  CRK; adapter molecule crk isoform X1 [KO:K04438]
102420269  CRKL; crk-like protein isoform X1 [KO:K04438]
102417583  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
102433625  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
102429987  EXOC7; exocyst complex component 7 [KO:K07195]
102417479  TRIP10; cdc42-interacting protein 4 [KO:K07196]
102441432  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102439451  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102422910  PKLR; LOW QUALITY PROTEIN: pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
102417861  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
102426995  HKDC1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
102441041  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
102425498  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
102436756  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
102440094  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102438720  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102430132  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
106695632  5'-AMP-activated protein kinase subunit beta-2-like [KO:K07199]
102430862  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102428212  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
102425288  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
102436674  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
102432268  FOXO1; LOW QUALITY PROTEIN: forkhead box protein O1 [KO:K07201]
102417838  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
102439281  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102425980  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102438112  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
102426329  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
102426019  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
102423798  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X2 [KO:K01596] [EC:4.1.1.32]
102430158  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
102434974  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102430610  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
102429245  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
102433676  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
102437206  RPS6; 40S ribosomal protein S6 [KO:K02991]
102418433  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
102437938  eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
102433516  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
102416807  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
102431191  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
102440346  TSC1; hamartin [KO:K07206]
102422720  TSC2; tuberin isoform X1 [KO:K07207]
102422024  LOW QUALITY PROTEIN: GTP-binding protein Rheb-like [KO:K07208]
102441557  RHEB; GTP-binding protein Rheb [KO:K07208]
102437980  BAD; bcl2-associated agonist of cell death [KO:K02158]
102430334  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
102435382  SHC3; LOW QUALITY PROTEIN: SHC-transforming protein 3 [KO:K17448]
102431548  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
102421027  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
102442926  SOS1; son of sevenless homolog 1 [KO:K03099]
102437531  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
102431999  KRAS; GTPase KRas isoform X1 [KO:K07827]
102430744  NRAS; GTPase NRas [KO:K07828]
102420799  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
102435241  BRAF; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
102434453  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102417411  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
102423748  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102417755  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102422236  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102440265  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X3 [KO:K04372] [EC:2.7.11.1]
102433509  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X13 [KO:K04372] [EC:2.7.11.1]
102419846  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
102441637  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
102426869  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
102424919  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102434218  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
102417949  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
102440978  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
102430582  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102437455  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102418507  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102417312  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X4 [KO:K07209] [EC:2.7.11.10]
102419220  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
102423116  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
mlf00010  Glycolysis / Gluconeogenesis
mlf00061  Fatty acid biosynthesis
mlf00500  Starch and sucrose metabolism
mlf04010  MAPK signaling pathway
mlf04070  Phosphatidylinositol signaling system
mlf04210  Apoptosis
KO pathway
ko04910   
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