KEGG   PATHWAY: clud04910
Entry
clud04910                   Pathway                                
Name
Insulin signaling pathway - Canis lupus dingo (dingo)
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
clud04910  Insulin signaling pathway
clud04910

Organism
Canis lupus dingo (dingo) [GN:clud]
Gene
112640050  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
112640112  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
112640159  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
112640373  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
112640520  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
112640546  TSC2; tuberin isoform X1 [KO:K07207]
112640987  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
112641257  FLOT1; flotillin-1 isoform X1 [KO:K07192]
112642541  MKNK1; LOW QUALITY PROTEIN: MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
112642563  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
112642635  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
112644609  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
112644610  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
112644865  SHC3; SHC-transforming protein 3 [KO:K17448]
112644896  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
112645175  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
112645263  CALM3; calmodulin-3 isoform X1 [KO:K02183]
112645376  LIPE; LOW QUALITY PROTEIN: hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
112645463  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
112645871  [KO:K02991]
112645941  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
112645948  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
112646074  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
112646190  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
112646871  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X5 [KO:K00922] [EC:2.7.1.153]
112646980  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
112646988  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
112647094  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
112647246  SREBF1; sterol regulatory element-binding protein 1 isoform X2 [KO:K07197]
112647488  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
112647577  [KO:K02991]
112648317  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
112648737  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
112648931  PKLR; pyruvate kinase PKLR isoform X2 [KO:K12406] [EC:2.7.1.40]
112648956  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
112649305  IRS4; insulin receptor substrate 4 [KO:K17446]
112650443  RPS6; 40S ribosomal protein S6 isoform X1 [KO:K02991]
112650698  GCK; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
112650991  BRAF; serine/threonine-protein kinase B-raf isoform X5 [KO:K04365] [EC:2.7.11.1]
112651170  HK3; hexokinase-3 isoform X2 [KO:K00844] [EC:2.7.1.1]
112651227  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
112651623  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
112651698  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
112651928  HK1; hexokinase-1 isoform X2 [KO:K00844] [EC:2.7.1.1]
112652680  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
112652918  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
112653713  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
112654092  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
112654340  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
112654846  [KO:K02991]
112655082  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
112655217  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
112655440  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
112655510  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
112655674  [KO:K02183]
112655863  IRS2; insulin receptor substrate 2 isoform X2 [KO:K07187]
112656000  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
112656570  [KO:K03259]
112656757  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X3 [KO:K07200]
112656863  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
112656872  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
112656898  CALM1; calmodulin-1 [KO:K02183]
112657245  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
112657991  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
112657995  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
112658031  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112658063  [KO:K02183]
112659017  [KO:K02183]
112659069  CALML5; calmodulin-like protein 5 [KO:K02183]
112659290  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
112659359  BAD; bcl2-associated agonist of cell death [KO:K02158]
112659369  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
112659381  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
112659577  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
112660199  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
112660557  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
112661215  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
112661330  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
112661394  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
112662621  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
112663225  INS; insulin [KO:K04526]
112663432  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
112663472  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
112663536  HRAS; GTPase HRas isoform X1 [KO:K02833]
112664082  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199]
112664166  NRAS; GTPase NRas [KO:K07828]
112664264  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
112664493  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
112664593  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
112665506  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
112665533  KRAS; GTPase KRas isoform X1 [KO:K07827]
112665758  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
112666141  SHC2; SHC-transforming protein 2 isoform X3 [KO:K17447]
112666215  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
112666294  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
112666386  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
112666443  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
112666468  [KO:K02991]
112666620  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
112666735  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
112667461  INPPL1; LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
112667669  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
112668280  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
112668849  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
112669083  [KO:K04371] [EC:2.7.11.24]
112669362  FOXO1; forkhead box protein O1 [KO:K07201]
112669817  IRS1; insulin receptor substrate 1 [KO:K16172]
112669908  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
112670774  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
112671204  CBL; E3 ubiquitin-protein ligase CBL isoform X2 [KO:K04707] [EC:2.3.2.27]
112671633  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
112671784  CALM2; calmodulin-2 isoform X3 [KO:K02183]
112671847  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
112671968  MAPK8; mitogen-activated protein kinase 8 isoform X3 [KO:K04440] [EC:2.7.11.24]
112672050  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
112672101  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X4 [KO:K06086]
112672530  INPP5A; inositol polyphosphate-5-phosphatase A isoform X2 [KO:K01106] [EC:3.1.3.56]
112672798  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
112672825  EXOC7; exocyst complex component 7 isoform X5 [KO:K07195]
112672873  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
112672911  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
112672967  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
112673111  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
112673245  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
112673250  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
112674115  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
112674170  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
112674210  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
112675698  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
112675721  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
112675960  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
112676539  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
112676653  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
112676715  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
112677012  CRKL; crk-like protein isoform X1 [KO:K04438]
112677029  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
112677353  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
112677368  TSC1; hamartin isoform X1 [KO:K07206]
112677583  CRK; adapter molecule crk isoform X1 [KO:K04438]
112677588  GSK3B; glycogen synthase kinase-3 beta isoform X3 [KO:K03083] [EC:2.7.11.26]
112677646  FLOT2; flotillin-2 isoform X1 [KO:K07192]
112677796  [KO:K02991]
112678102  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
112678282  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X3 [KO:K07200]
112679007  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
118351175  [KO:K02991]
118354148  [KO:K02991]
125754135  [KO:K04695]
125754673  [KO:K03259]
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
clud00010  Glycolysis / Gluconeogenesis
clud00061  Fatty acid biosynthesis
clud00500  Starch and sucrose metabolism
clud04010  MAPK signaling pathway
clud04070  Phosphatidylinositol signaling system
clud04210  Apoptosis
KO pathway
ko04910   

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