KEGG   PATHWAY: ccan04910
Entry
ccan04910                   Pathway                                
Name
Insulin signaling pathway - Castor canadensis (American beaver)
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
ccan04910  Insulin signaling pathway
ccan04910

Organism
Castor canadensis (American beaver) [GN:ccan]
Gene
109674302  [KO:K02183]
109674563  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
109674958  [KO:K02183]
109675517  Irs4; insulin receptor substrate 4 [KO:K17446]
109675955  Shc3; SHC-transforming protein 3 [KO:K17448]
109676152  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
109676553  Socs1; LOW QUALITY PROTEIN: suppressor of cytokine signaling 1 [KO:K04694]
109677759  Phkg1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
109679334  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
109680203  [KO:K02183]
109680387  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
109681298  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
109681355  Prkar2b; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
109681560  Ptprf; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
109681589  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
109681591  Sh2b2; LOW QUALITY PROTEIN: SH2B adapter protein 2 [KO:K07193]
109681900  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109682021  [KO:K04365] [EC:2.7.11.1]
109682432  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109682498  Phkg2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
109682554  [KO:K02649]
109682600  Crk; adapter molecule crk isoform X1 [KO:K04438]
109682693  [KO:K00693] [EC:2.4.1.11]
109683139  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
109683259  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
109683261  Bad; bcl2-associated agonist of cell death [KO:K02158]
109683414  Fbp1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
109683422  Fbp2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
109683487  Exoc7; exocyst complex component 7 isoform X1 [KO:K07195]
109684212  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
109684252  Shc4; SHC-transforming protein 4 [KO:K17449]
109684371  Crkl; crk-like protein isoform X1 [KO:K04438]
109684381  Mapk1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
109684503  [KO:K04739]
109684826  Phka2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
109684858  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
109684938  Hkdc1; LOW QUALITY PROTEIN: putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
109685124  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
109685239  Hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
109685242  Sos1; son of sevenless homolog 1 [KO:K03099]
109685265  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
109685266  Rheb; GTP-binding protein Rheb [KO:K07208]
109685333  Gsk3b; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
109685544  [KO:K06269] [EC:3.1.3.16]
109685772  Hk3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
109685780  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
109685901  Gck; glucokinase [KO:K12407] [EC:2.7.1.2]
109686083  Shc2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
109686235  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109686538  [KO:K03099]
109686727  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
109686728  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
109686738  [KO:K04440] [EC:2.7.11.24]
109687060  Kras; GTPase KRas [KO:K07827]
109687176  Pygm; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
109687214  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
109687258  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
109687316  G6pc; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
109687808  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
109687824  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109687830  [KO:K07190]
109687970  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
109688030  Shc1; LOW QUALITY PROTEIN: SHC-transforming protein 1 [KO:K06279]
109688234  Calml4; calmodulin-like protein 4 [KO:K02183]
109688536  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109688624  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
109688628  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
109688701  [KO:K04345] [EC:2.7.11.11]
109688706  [KO:K04345] [EC:2.7.11.11]
109688720  Ppp1r3f; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
109688786  Socs2; suppressor of cytokine signaling 2 [KO:K04695]
109688921  Foxo1; LOW QUALITY PROTEIN: forkhead box protein O1 [KO:K07201]
109688934  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
109689226  G6pc2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
109689448  Ppp1r3b; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
109689545  G6pc3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
109689656  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109689664  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109689794  [KO:K04526]
109689889  Rptor; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
109689940  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
109690162  Tsc2; tuberin isoform X1 [KO:K07207]
109690552  Acacb; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109690560  Ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
109691000  Tsc1; LOW QUALITY PROTEIN: hamartin [KO:K07206]
109691221  Calm3; calmodulin [KO:K02183]
109691439  Prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
109691449  Calml6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
109691630  Ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
109691756  [KO:K02183]
109691810  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109691865  Lipe; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
109691895  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
109691989  Prkar2a; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
109692285  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
109693012  Inppl1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
109693529  Flot1; flotillin-1 [KO:K07192]
109693543  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
109693652  Sorbs1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
109693916  [KO:K07190]
109693954  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
109694006  Insr; LOW QUALITY PROTEIN: insulin receptor [KO:K04527] [EC:2.7.10.1]
109694666  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
109694818  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
109694940  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
109695445  Pde3b; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
109695455  Acaca; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109695463  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
109695645  Flot2; flotillin-2 isoform X1 [KO:K07192]
109695664  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
109696062  Nras; GTPase NRas [KO:K07828]
109696161  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
109696224  Cbl; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
109696281  Calm2; calmodulin [KO:K02183]
109696372  Ppp1r3a; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
109696400  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
109696597  Ptpn1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
109696670  Araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
109696675  Elk1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
109696750  Irs1; LOW QUALITY PROTEIN: insulin receptor substrate 1 [KO:K16172]
109696888  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
109697774  Ppp1r3e; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
109697922  Hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
109698042  Hras; GTPase HRas isoform X1 [KO:K02833]
109698062  [KO:K17445]
109698290  [KO:K04372] [EC:2.7.11.1]
109698298  Rps6; 40S ribosomal protein S6 [KO:K02991]
109698635  Inpp5a; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [KO:K01106] [EC:3.1.3.56]
109698713  Trip10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
109698867  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
109698982  [KO:K04365] [EC:2.7.11.1]
109699003  Cblb; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
109699140  Calm1; calmodulin [KO:K02183]
109699830  Pygb; LOW QUALITY PROTEIN: glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
109700146  Rhoq; rho-related GTP-binding protein RhoQ [KO:K07194]
109700210  Prkci; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
109700840  Calml5; calmodulin-like protein 5 [KO:K02183]
109700844  [KO:K02183]
109700908  [KO:K02183]
109700963  Irs2; insulin receptor substrate 2 [KO:K07187]
109701350  Prkar1a; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
109701447  Srebf1; sterol regulatory element-binding protein 1 [KO:K07197]
109702407  Fasn; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
109703004  [KO:K04440] [EC:2.7.11.24]
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
ccan00010  Glycolysis / Gluconeogenesis
ccan00061  Fatty acid biosynthesis
ccan00500  Starch and sucrose metabolism
ccan04010  MAPK signaling pathway
ccan04070  Phosphatidylinositol signaling system
ccan04210  Apoptosis
KO pathway
ko04910   

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