KEGG   PATHWAY: aamp04910
Entry
aamp04910                   Pathway                                
Name
Insulin signaling pathway - Arvicola amphibius (Eurasian water 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
aamp04910  Insulin signaling pathway
aamp04910

Organism
Arvicola amphibius (Eurasian water vole) [GN:aamp]
Gene
119805421  Ins; insulin [KO:K04526]
119825604  Insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
119820738  Irs1; insulin receptor substrate 1 [KO:K16172]
119813278  Irs2; insulin receptor substrate 2 [KO:K07187]
119824895  insulin receptor substrate 1-like [KO:K17445]
119805566  Irs4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
119808979  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
119817743  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
119812102  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
119816315  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
119810503  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
119826317  Pik3ca; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
119813044  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
119818643  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
119820487  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
119827246  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
119824224  Gsk3b; LOW QUALITY PROTEIN: glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
119808488  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
119802804  Gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
119801984  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
119804974  serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269] [EC:3.1.3.16]
119825387  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
119807529  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
119808444  Ppp1r3a; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3A [KO:K07189]
119815667  Ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
119802581  Ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
119812582  Ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
119800148  Ppp1r3e; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
119805527  Ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
119825273  Phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
119807018  Phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
119801764  Phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
119804574  Phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
119804692  Phka1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
119821021  Calm3; calmodulin-3 [KO:K02183]
119808332  Calm2; calmodulin-2 [KO:K02183]
119808754  Calml4; calmodulin-like protein 4 [KO:K02183]
119809106  calmodulin-1 [KO:K02183]
119815477  calmodulin-1 [KO:K02183]
119817551  Calml3; calmodulin-like protein 3 [KO:K02183]
119817552  calmodulin-4-like [KO:K02183]
119818370  Calm1; calmodulin-1 [KO:K02183]
119814546  Pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
119814614  Pygm; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
119818423  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
119807439  Pde3b; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
119800975  Prkacb; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
119802004  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
119810173  Prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
119811913  Prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
119818740  Prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
119825300  Prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
119820308  Lipe; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
119816609  Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
119826655  Prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
119812189  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
119822742  Flot1; flotillin-1 [KO:K07192]
119811914  Flot2; flotillin-2 isoform X1 [KO:K07192]
119825332  Sh2b2; SH2B adapter protein 2 [KO:K07193]
119817058  Sorbs1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
119809631  Cbl; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
119824571  Cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
119811835  Crk; adapter molecule crk isoform X1 [KO:K04438]
119824768  Crkl; crk-like protein [KO:K04438]
119818619  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
119806849  Rhoq; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
119811839  Exoc7; exocyst complex component 7 [KO:K07195]
119803116  Trip10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
119812590  Srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
119811154  Acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
119824641  Acacb; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
119811347  Fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
119801202  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
119822689  Hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
119822980  Hkdc1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
119817811  Hk3; LOW QUALITY PROTEIN: hexokinase-3 [KO:K00844] [EC:2.7.1.1]
119806784  Hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
119820164  Gck; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
119816370  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
119810200  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
119801352  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
119825157  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
119820999  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
119822790  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
119806497  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
119826452  Foxo1; forkhead box protein O1 [KO:K07201]
119809862  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
119819699  G6pc2; LOW QUALITY PROTEIN: glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
119812167  G6pc1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
119812873  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
119817030  Fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
119817693  Fbp1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
119814634  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
119800022  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
119816408  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
119813137  Rptor; LOW QUALITY PROTEIN: regulatory-associated protein of mTOR [KO:K07204]
119814876  Rps6kb2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
119813254  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
119821193  40S ribosomal protein S6-like [KO:K02991]
119818034  Rps6; 40S ribosomal protein S6 [KO:K02991]
119807118  40S ribosomal protein S6-like [KO:K02991]
119800250  40S ribosomal protein S6-like [KO:K02991]
119813700  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
119801210  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
119817130  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
119805270  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-like [KO:K03259]
119805282  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-like [KO:K03259]
119826625  eukaryotic translation initiation factor 4E-like [KO:K03259]
119820579  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
119818627  Tsc1; hamartin isoform X1 [KO:K07206]
119811857  Tsc2; tuberin isoform X1 [KO:K07207]
119807890  Rheb; GTP-binding protein Rheb [KO:K07208]
119820525  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
119800744  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
119825434  Shc2; SHC-transforming protein 2 [KO:K17447]
119817129  Shc3; SHC-transforming protein 3 [KO:K17448]
119815646  Shc4; SHC-transforming protein 4 isoform X1 [KO:K17449]
119813014  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
119818434  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
119806329  Sos1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
119800249  Hras; GTPase HRas isoform X1 [KO:K02833]
119804230  GTPase KRas-like [KO:K07827]
119806318  Kras; GTPase KRas isoform X1 [KO:K07827]
119801497  Nras; GTPase NRas [KO:K07828]
119805132  Araf; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
119806667  Braf; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
119808272  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
119805902  LOW QUALITY PROTEIN: RAF proto-oncogene serine/threonine-protein kinase-like [KO:K04366] [EC:2.7.11.1]
119809903  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
119827491  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
119824680  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
119813356  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
119816390  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
119817893  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
119804537  Elk1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
119813226  Socs1; suppressor of cytokine signaling 1 [KO:K04694]
119803710  Socs2; LOW QUALITY PROTEIN: suppressor of cytokine signaling 2 [KO:K04695]
119812431  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
119800354  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
119814862  Ptpn1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
119816980  Ptprf; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
119811270  Mapk9; LOW QUALITY PROTEIN: mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
119813574  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
119827427  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
119812324  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
119821992  Inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
119817202  Inpp5a; inositol polyphosphate-5-phosphatase A [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
aamp00010  Glycolysis / Gluconeogenesis
aamp00061  Fatty acid biosynthesis
aamp00500  Starch and sucrose metabolism
aamp04010  MAPK signaling pathway
aamp04070  Phosphatidylinositol signaling system
aamp04210  Apoptosis
KO pathway
ko04910   
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