KEGG   PATHWAY: prob04910
Entry
prob04910                   Pathway                                
Name
Insulin signaling pathway - Phodopus roborovskii (desert hamster)
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
prob04910  Insulin signaling pathway
prob04910

Organism
Phodopus roborovskii (desert hamster) [GN:prob]
Gene
127237189  Insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
127226500  Irs1; insulin receptor substrate 1 [KO:K16172]
127220248  Irs2; insulin receptor substrate 2 [KO:K07187]
127237201  insulin receptor substrate 1 [KO:K17445]
127217141  Irs4; insulin receptor substrate 4 [KO:K17446]
127217216  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
127225197  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
127220972  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
127223328  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
127238024  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
127213428  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
127219578  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
127223664  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
127231187  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
127239025  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
127227159  Gsk3b; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
127215592  LOW QUALITY PROTEIN: glycogen [starch] synthase, liver-like [KO:K00693] [EC:2.4.1.11]
127213091  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
127213697  Gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
127216061  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
127228640  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
127220109  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
127222756  Ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
127230404  Ppp1r3e; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
127220423  Ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
127233220  Ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
127215329  Ppp1r3a; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
127218369  Ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
127228393  Phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
127237009  Phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
127229936  Phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
127217902  Phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
127217938  Phka1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
127223580  calmodulin-alpha-like [KO:K02183]
127229809  calmodulin-like protein 3 [KO:K02183]
127229810  Calml5; calmodulin-like protein 5 [KO:K02183]
127231063  Calm1; calmodulin-1 [KO:K02183]
127231862  Calml4; calmodulin-like protein 4 [KO:K02183]
127238587  Calm3; calmodulin-3 [KO:K02183]
127213474  Calml6; calmodulin-like protein 6 [KO:K02183]
127214928  Calm2; calmodulin-2 [KO:K02183]
127228731  Pygm; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
127228866  Pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
127230657  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
127228213  Pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B [KO:K13296] [EC:3.1.4.17]
127229872  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
127229917  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
127236385  Prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
127218628  Prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
127237324  Prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
127214871  Prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
127238774  hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
127213543  Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
127223347  Prkci; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
127219033  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
127224364  Flot1; flotillin-1 isoform X1 [KO:K07192]
127218864  Flot2; flotillin-2 isoform X1 [KO:K07192]
127236969  Sh2b2; SH2B adapter protein 2 [KO:K07193]
127233398  Sorbs1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
127231592  Cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
127227249  Cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
127218905  Crk; adapter molecule crk isoform X1 [KO:K04438]
127226930  Crkl; crk-like protein [KO:K04438]
127222690  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
127214923  Rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
127219438  Exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
127216804  Trip10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
127219200  Srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
127221108  Acaca; acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
127215967  Acacb; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
127220557  Fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
127232814  Pklr; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
127229204  Hk3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
127235467  Hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
127224002  Hk1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
127224033  Hkdc1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
127233921  Gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
127224997  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
127220610  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
127216002  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
127233006  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
127235796  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
127226041  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
127226445  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
127216298  Foxo1; forkhead box protein O1 [KO:K07201]
127213598  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
127221880  G6pc2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
127216693  G6pc1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
127217401  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
127229132  Fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
127229133  Fbp1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
127222798  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
127230385  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
127213510  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
127220055  Rptor; regulatory-associated protein of mTOR [KO:K07204]
127228636  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
127224001  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
127236638  40S ribosomal protein S6 [KO:K02991]
127224923  Rps6; 40S ribosomal protein S6 [KO:K02991]
127220381  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
127222941  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
127223139  eukaryotic translation initiation factor 4E [KO:K03259]
127229419  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
127224934  eukaryotic translation initiation factor 4E-like [KO:K03259]
127226654  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
127227013  eukaryotic translation initiation factor 4E [KO:K03259]
127222678  Tsc1; hamartin isoform X1 [KO:K07206]
127219556  Tsc2; tuberin isoform X1 [KO:K07207]
127235802  Rheb; GTP-binding protein Rheb [KO:K07208]
127228773  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
127233113  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
127216670  Shc2; SHC-transforming protein 2 [KO:K17447]
127229241  Shc3; SHC-transforming protein 3 [KO:K17448]
127221520  Shc4; SHC-transforming protein 4 [KO:K17449]
127219174  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
127217013  Sos1; son of sevenless homolog 1 [KO:K03099]
127230645  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
127228530  Hras; GTPase HRas [KO:K02833]
127213087  Kras; GTPase KRas isoform X1 [KO:K07827]
127233129  Nras; GTPase NRas [KO:K07828]
127214235  Braf; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
127236205  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
127231875  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
127216563  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
127228340  Mapk3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
127216731  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
127226948  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
127216606  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
127225188  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
127218479  Elk1; ETS domain-containing protein Elk-1 [KO:K04375]
127223018  LOW QUALITY PROTEIN: suppressor of cytokine signaling 1-like [KO:K04694]
127219667  Socs1; LOW QUALITY PROTEIN: suppressor of cytokine signaling 1 [KO:K04694]
127237871  Socs2; suppressor of cytokine signaling 2 [KO:K04695]
127219795  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
127216418  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
127223333  Ptpn1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
127225248  Ptprf; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
127235390  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
127219360  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
127232178  Mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
127220313  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
127227993  Inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
127228490  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
  Authors
Ogawa W, Kasuga M.
  Title
[Mechanism of insulin action and diabetes mellitus]
  Journal
Seikagaku 75:1332-44 (2003)
Reference
  Authors
Bevan P.
  Title
Insulin signalling.
  Journal
J Cell Sci 114:1429-30 (2001)
Reference
  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
  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
  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
  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
  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
  Authors
Ruggero D, Sonenberg N.
  Title
The Akt of translational control.
  Journal
Oncogene 24:7426-34 (2005)
DOI:10.1038/sj.onc.1209098
Reference
  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
  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
  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
  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
  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
  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
prob00010  Glycolysis / Gluconeogenesis
prob00061  Fatty acid biosynthesis
prob00500  Starch and sucrose metabolism
prob04010  MAPK signaling pathway
prob04070  Phosphatidylinositol signaling system
prob04210  Apoptosis
KO pathway
ko04910   
LinkDB

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