KEGG   PATHWAY: cfa04910
Entry
cfa04910                    Pathway                                
Name
Insulin signaling pathway - Canis lupus familiaris (dog)
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
cfa04910  Insulin signaling pathway
cfa04910

Organism
Canis lupus familiaris (dog) [GN:cfa]
Gene
483665  INS; insulin precursor [KO:K04526]
484990  INSR; insulin receptor isoform X3 [KO:K04527] [EC:2.7.10.1]
486148  IRS1; insulin receptor substrate 1 [KO:K16172]
485548  IRS2; insulin receptor substrate 2 isoform X8 [KO:K07187]
492059  IRS4; insulin receptor substrate 4 [KO:K17446]
609956  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
487235  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100856339  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
488084  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
489644  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
477085  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
479875  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X3 [KO:K06276] [EC:2.7.11.1]
442964  AKT3; RAC-gamma serine/threonine-protein kinase isoform X8 [KO:K04456] [EC:2.7.11.1]
449021  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
490878  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
478575  GSK3B; glycogen synthase kinase-3 beta isoform X13 [KO:K03083] [EC:2.7.11.26]
403737  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
611993  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
403557  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
403558  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
403609  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
485953  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
482881  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
482411  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X5 [KO:K07189]
477766  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
490610  PPP1R3E; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
491877  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X2 [KO:K17453]
489784  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
607275  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
478139  PHKB; phosphorylase b kinase regulatory subunit beta isoform X2 [KO:K07190]
491956  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X20 [KO:K07190]
474584  CALM2; calmodulin-2 [KO:K02183]
607269  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
487146  CALML5; calmodulin-like protein 5 [KO:K02183]
480416  CALM1; calmodulin-1 [KO:K02183]
476428  CALM3; calmodulin-3 isoform X2 [KO:K02183]
478351  CALML4; calmodulin-like protein 4 isoform X2 [KO:K02183]
102153034  calmodulin-like protein 3 [KO:K02183]
611078  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
403738  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
477003  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
611730  PDE3B; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X2 [KO:K13296] [EC:3.1.4.17]
403556  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
479975  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
475887  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
480459  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
480805  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X2 [KO:K04739]
100685147  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
403607  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
479577  PRKCZ; protein kinase C zeta type isoform X5 [KO:K18952] [EC:2.7.11.13]
478686  PRKCI; protein kinase C iota type isoform X2 [KO:K06069] [EC:2.7.11.13]
403673  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
474831  FLOT1; flotillin-1 isoform X1 [KO:K07192]
100856195  FLOT2; flotillin-2 isoform X1 [KO:K07192]
489820  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
100686806  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X14 [KO:K06086]
489369  CBL; E3 ubiquitin-protein ligase CBL isoform X2 [KO:K04707] [EC:2.3.2.27]
487965  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
608125  CRKL; crk-like protein isoform X2 [KO:K04438]
100684309  CRK; adapter molecule crk isoform X8 [KO:K04438]
491286  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
474579  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
100682715  EXOC7; exocyst complex component 7 isoform X5 [KO:K07195]
476726  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
403475  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
491130  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100685468  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
483378  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
490425  PKLR; pyruvate kinase PKLR isoform 1 [KO:K12406] [EC:2.7.1.40]
489096  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
479234  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
489019  HKDC1; hexokinase HKDC1 isoform X5 [KO:K00844] [EC:2.7.1.1]
100856448  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
606490  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
479351  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
489571  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X2 [KO:K07198] [EC:2.7.11.31]
486295  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100856379  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
475546  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
486559  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
488526  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
477295  FOXO1; forkhead box protein O1 [KO:K07201]
479127  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
403492  G6PC1; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
488389  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
490942  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
476300  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
476299  FBP1; fructose-1,6-bisphosphatase 1 isoform X2 [KO:K03841] [EC:3.1.3.11]
403560  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
480255  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
478232  MTOR; serine/threonine-protein kinase mTOR isoform X5 [KO:K07203] [EC:2.7.11.1]
608378  RPTOR; regulatory-associated protein of mTOR isoform X2 [KO:K07204]
480580  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X3 [KO:K04688] [EC:2.7.11.1]
610499  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
474722  RPS6; 40S ribosomal protein S6 [KO:K02991]
488146  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
100686736  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
106559872  40S ribosomal protein S6-like [KO:K02991]
608772  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like isoform X4 [KO:K02991]
475590  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
487870  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
610238  EIF4E2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
489099  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
611215  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
100685582  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
480688  TSC1; hamartin isoform X1 [KO:K07206]
479883  TSC2; tuberin isoform X1 [KO:K07207]
475545  RHEB; GTP-binding protein Rheb isoform X2 [KO:K07208]
483763  BAD; bcl2-associated agonist of cell death [KO:K02158]
490439  SHC1; SHC-transforming protein 1 [KO:K06279]
611955  SHC2; SHC-transforming protein 2 isoform X2 [KO:K17447]
476352  SHC3; SHC-transforming protein 3 [KO:K17448]
487546  SHC4; SHC-transforming protein 4 isoform X2 [KO:K17449]
483312  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
490682  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
403735  HRAS; GTPase HRas isoform 1 [KO:K02833]
403871  KRAS; GTPase KRas isoform X1 [KO:K07827]
403872  NRAS; GTPase NRas [KO:K07828]
491857  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
475526  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
484648  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
478347  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
611939  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
477575  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100855877  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
612212  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
482509  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X2 [KO:K04372] [EC:2.7.11.1]
491860  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
490006  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
100855737  SOCS2; suppressor of cytokine signaling 2 isoform X3 [KO:K04695]
442949  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100687271  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
477263  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X12 [KO:K05696] [EC:3.1.3.48]
475389  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X25 [KO:K05695] [EC:3.1.3.48]
477746  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
478464  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
474652  MAPK9; mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
482839  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
485209  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
403937  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
cfa00010  Glycolysis / Gluconeogenesis
cfa00061  Fatty acid biosynthesis
cfa00500  Starch and sucrose metabolism
cfa04010  MAPK signaling pathway
cfa04070  Phosphatidylinositol signaling system
cfa04210  Apoptosis
KO pathway
ko04910   

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Genome (1)   
   KEGG GENOME (1)   
Gene (140)   
   KEGG GENES (140)   
All databases (141)   

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