KEGG   PATHWAY: anu04910
Entry
anu04910                    Pathway                                
Name
Insulin signaling pathway - Arvicanthis niloticus (African grass rat)
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
anu04910  Insulin signaling pathway
anu04910

Organism
Arvicanthis niloticus (African grass rat) [GN:anu]
Gene
117722990  insulin-2 isoform X1 [KO:K04526]
117723507  insulin-2 [KO:K04526]
117697878  Insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
117722352  Irs1; insulin receptor substrate 1 [KO:K16172]
117721708  Irs2; insulin receptor substrate 2 [KO:K07187]
117698147  insulin receptor substrate 1-like [KO:K17445]
117695265  Irs4; insulin receptor substrate 4 [KO:K17446]
117721973  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
117723761  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
117708961  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
117706649  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
117693421  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
117708986  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
117710000  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
117697536  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
117706636  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117721481  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
117718295  Gsk3b; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
117714877  Gys1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
117715222  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
117714791  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
117697837  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
117716888  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
117722079  Ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
117705992  Ppp1r3e; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
117720751  Ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
117704008  Ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
117720902  Ppp1r3a; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
117694852  Ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
117714976  Phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
117697985  Phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
117723492  Phkb; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
117694487  Phka1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
117695387  Phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
117722538  calmodulin-1-like [KO:K02183]
117697522  Calm1; calmodulin-1 [KO:K02183]
117715216  calmodulin-1-like [KO:K02183]
117716931  Calm2; calmodulin-2 [KO:K02183]
117699053  Calml4; calmodulin-like protein 4 isoform X1 [KO:K02183]
117700456  Calm3; calmodulin-3 [KO:K02183]
117713333  Calml3; calmodulin-like protein 3 [KO:K02183]
117713892  Calml5; calmodulin-like protein 5 [KO:K02183]
117704513  Pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
117717246  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
117709985  Pygm; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
117696410  Pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
117723055  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
117706647  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
117697833  Prkar1b; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
117717122  Prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
117693211  Prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
117710430  Prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
117720546  Lipe; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
117708435  Prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
117706861  Prkci; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
117711148  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
117724572  Flot1; flotillin-1 [KO:K07192]
117710725  Flot2; flotillin-2 isoform X1 [KO:K07192]
117697961  Sh2b2; SH2B adapter protein 2 [KO:K07193]
117714347  Sorbs1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
117698924  Cbl; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
117717744  Cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
117717801  Crkl; crk-like protein [KO:K04438]
117710148  Crk; adapter molecule crk isoform X1 [KO:K04438]
117703002  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
117717278  Rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
117710097  Exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
117705398  Trip10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
117711604  Srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
117709906  Acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
117698256  Acacb; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
117710072  Fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
117707155  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
117715071  Hk2; LOW QUALITY PROTEIN: hexokinase-2 [KO:K00844] [EC:2.7.1.1]
117724458  Hkdc1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
117724695  Hk1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
117713920  Hk3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
117712800  Gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
117723868  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
117708512  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
117698037  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
117707094  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
117705444  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
117719091  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
117720702  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
117706979  Foxo1; forkhead box protein O1 [KO:K07201]
117712664  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
117711869  G6pc; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
117709844  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
117704199  G6pc2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
117713746  Fbp1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
117713747  Fbp2; fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
117706152  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
117703545  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
117709409  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
117710599  Rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
117710017  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
117714029  Rps6kb2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
117708970  Rps6; 40S ribosomal protein S6 [KO:K02991]
117721241  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
117722342  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
117706990  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
117714026  Eif4e1b; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
117703026  Tsc1; hamartin isoform X1 [KO:K07206]
117710404  Tsc2; tuberin isoform X1 [KO:K07207]
117694570  GTP-binding protein Rheb-like [KO:K07208]
117694603  GTP-binding protein Rheb-like [KO:K07208]
117720863  Rheb; GTP-binding protein Rheb [KO:K07208]
117706557  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
117706686  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
117696653  Shc2; SHC-transforming protein 2 [KO:K17447]
117713721  Shc3; SHC-transforming protein 3 [KO:K17448]
117704137  Shc4; SHC-transforming protein 4 [KO:K17449]
117711195  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
117716781  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
117716983  Sos1; son of sevenless homolog 1 isoform X1 [KO:K03099]
117706664  Hras; GTPase HRas isoform X1 [KO:K02833]
117714902  Kras; GTPase KRas isoform X1 [KO:K07827]
117706966  Nras; GTPase NRas [KO:K07828]
117694504  Araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
117721084  Braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
117715476  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
117699009  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
117696143  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
117717711  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
117693439  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
117708566  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
117696340  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
117694184  Elk1; ETS domain-containing protein Elk-1 [KO:K04375]
117711308  Socs1; suppressor of cytokine signaling 1 [KO:K04694]
117696875  Socs2; suppressor of cytokine signaling 2 [KO:K04695]
117711957  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
117705978  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
117703085  Ptpn1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
117708182  Ptprf; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
117705037  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
117709966  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
117721547  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
117708562  Inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
117715712  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
anu00010  Glycolysis / Gluconeogenesis
anu00061  Fatty acid biosynthesis
anu00500  Starch and sucrose metabolism
anu04010  MAPK signaling pathway
anu04070  Phosphatidylinositol signaling system
anu04210  Apoptosis
KO pathway
ko04910   
LinkDB

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