KEGG   PATHWAY: morg04910
Entry
morg04910                   Pathway                                
Name
Insulin signaling pathway - Microtus oregoni (creeping vole)
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
morg04910  Insulin signaling pathway
morg04910

Organism
Microtus oregoni (creeping vole) [GN:morg]
Gene
121457317  Ins; insulin [KO:K04526]
121465153  Insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
121446925  Irs1; insulin receptor substrate 1 [KO:K16172]
121462188  Irs2; insulin receptor substrate 2 [KO:K07187]
121446140  insulin receptor substrate 1-like [KO:K17445]
121436878  LOW QUALITY PROTEIN: insulin receptor substrate 4-like [KO:K17446]
121437242  LOW QUALITY PROTEIN: insulin receptor substrate 4-like [KO:K17446]
121455952  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
121462841  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
121448002  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
121464321  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
121453059  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
121448116  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
121441780  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform-like [KO:K00922] [EC:2.7.1.153]
121463628  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
121434429  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
121449224  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
121435875  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
121461919  Gsk3b; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
121437846  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
121449491  Gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
121454539  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
121446369  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
121432896  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
121454664  Ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
121462433  Ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
121463405  Ppp1r3a; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
121440816  Ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
121434844  Ppp1r3e; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
121444349  Ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
121442623  LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3F-like [KO:K17453]
121458032  Phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
121445879  Phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
121444664  phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
121446799  Phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
121441239  Phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
121441299  LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, liver isoform-like [KO:K07190]
121442853  LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform-like [KO:K07190]
121462368  calmodulin-1 [KO:K02183]
121465992  Calml4; calmodulin-like protein 4 isoform X1 [KO:K02183]
121432548  Calml5; calmodulin-like protein 5 isoform X1 [KO:K02183]
121432747  calmodulin-like protein 3 [KO:K02183]
121432887  Calm2; calmodulin-2 [KO:K02183]
121434435  Calm1; calmodulin-1 [KO:K02183]
121449209  Calm3; calmodulin-3 [KO:K02183]
121454032  Pygm; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
121452461  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
121460263  Pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
121457850  Pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
121455756  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
121451033  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
121464244  Prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
121452423  Prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
121436120  Prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
121446036  Prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
121450098  Lipe; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
121448043  protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
121443525  protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
121452820  Prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
121456757  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
121456948  Flot2; flotillin-2 isoform X1 [KO:K07192]
121435418  Flot1; flotillin-1 [KO:K07192]
121446127  Sh2b2; SH2B adapter protein 2 [KO:K07193]
121453966  Sorbs1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
121438406  Cbl; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
121461747  Cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
121456193  Crk; adapter molecule crk isoform X1 [KO:K04438]
121464797  Crkl; crk-like protein [KO:K04438]
121462617  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
121432852  Rhoq; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
121436300  Exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
121459727  Trip10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
121456564  Srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
121456289  Acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
121446056  Acacb; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
121444071  fatty acid synthase-like isoform X1 [KO:K00665] [EC:2.3.1.85]
121444583  fatty acid synthase [KO:K00665] [EC:2.3.1.85]
121450778  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
121453383  Hk3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
121450606  Hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
121450966  Hkdc1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
121435398  Hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
121459576  Gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
121432949  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
121447974  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
121438000  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
121446539  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
121439948  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
121447397  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
121441426  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
121452809  Foxo1; forkhead box protein O1 [KO:K07201]
121442270  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
121442435  G6pc1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
121435992  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
121453372  fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
121453487  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
121443370  fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
121443387  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
121440880  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
121435017  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
121448014  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
121441746  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
121436133  Rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
121444089  regulatory-associated protein of mTOR-like [KO:K07204]
121454174  Rps6kb2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
121457121  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
121454447  40S ribosomal protein S6-like [KO:K02991]
121455927  40S ribosomal protein S6-like [KO:K02991]
121455946  40S ribosomal protein S6-like [KO:K02991]
121452391  40S ribosomal protein S6-like [KO:K02991]
121440057  40S ribosomal protein S6-like [KO:K02991]
121441148  40S ribosomal protein S6-like [KO:K02991]
121448763  Rps6; 40S ribosomal protein S6 [KO:K02991]
121462285  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
121453231  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
121451055  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
121447053  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
121462616  Tsc1; hamartin isoform X1 [KO:K07206]
121463682  Tsc2; tuberin isoform X1 [KO:K07207]
121439898  Rheb; GTP-binding protein Rheb [KO:K07208]
121454562  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
121450478  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
121445583  SHC-transforming protein 1-like [KO:K06279]
121459499  Shc2; SHC-transforming protein 2 [KO:K17447]
121453450  SHC-transforming protein 3 [KO:K17448]
121445378  SHC-transforming protein 3-like [KO:K17448]
121465649  Shc4; SHC-transforming protein 4 isoform X1 [KO:K17449]
121463365  growth factor receptor-bound protein 2-like [KO:K04364]
121436142  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
121452307  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
121432861  Sos1; son of sevenless homolog 1 isoform X1 [KO:K03099]
121458090  Hras; GTPase HRas [KO:K02833]
121466497  Kras; GTPase KRas isoform X1 [KO:K07827]
121437938  Nras; GTPase NRas [KO:K07828]
121463309  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
121435346  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
121443425  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
121466018  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
121459389  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
121458143  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
121464725  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
121459340  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
121448556  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
121452930  ETS domain-containing protein Elk-1-like [KO:K04375]
121449131  ETS domain-containing protein Elk-1 [KO:K04375]
121463807  Socs1; suppressor of cytokine signaling 1 [KO:K04694]
121460345  Socs2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
121435989  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
121435011  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
121460249  Ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
121448826  Ptprf; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
121455025  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
121456117  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
121440925  Mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
121462326  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
121463745  Inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
121457556  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
morg00010  Glycolysis / Gluconeogenesis
morg00061  Fatty acid biosynthesis
morg00500  Starch and sucrose metabolism
morg04010  MAPK signaling pathway
morg04070  Phosphatidylinositol signaling system
morg04210  Apoptosis
KO pathway
ko04910   
LinkDB

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