KEGG   PATHWAY: shr04910
Entry
shr04910                    Pathway                                
Name
Insulin signaling pathway - Sarcophilus harrisii (Tasmanian devil)
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
shr04910  Insulin signaling pathway
shr04910

Organism
Sarcophilus harrisii (Tasmanian devil) [GN:shr]
Gene
100929204  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
100918116  IRS1; insulin receptor substrate 1 [KO:K16172]
100924829  IRS2; insulin receptor substrate 2 [KO:K07187]
100931354  IRS4; insulin receptor substrate 4 [KO:K07187]
100926892  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100924976  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
100935230  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100929811  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100932099  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105749979  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100917568  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100917987  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100913262  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100925440  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100920192  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100918400  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100920298  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
100930570  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100915116  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100920526  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
100928857  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
100915175  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
100931880  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
100927896  protein phosphatase 1 regulatory subunit 3C-like [KO:K07189]
100934815  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
116421814  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100928332  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
100920220  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
100927663  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
100922305  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
100923997  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
100926705  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
100929017  CALM1; calmodulin-1 isoform X2 [KO:K02183]
100920429  CALM2; calmodulin-2 [KO:K02183]
105750699  calmodulin-A [KO:K02183]
100935134  CALM3; calmodulin-3 isoform X1 [KO:K02183]
100925046  CALML4; calmodulin-like protein 4 [KO:K02183]
116419081  calmodulin [KO:K02183]
116423459  calmodulin-like [KO:K02183]
116423460  calmodulin-like [KO:K02183]
100934831  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
100927566  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100915891  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100934547  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
100929360  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100915481  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100934183  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
100913731  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
100916139  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
100925241  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit isoform X1 [KO:K04739]
100919924  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
100931671  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
100926393  LIPE; hormone-sensitive lipase [KO:K07188] [EC:3.1.1.79]
100916377  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100925605  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
100929154  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100917958  FLOT1; flotillin-1 isoform X1 [KO:K07192]
100933232  FLOT2; flotillin-2 isoform X1 [KO:K07192]
100929846  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
100914931  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
100920890  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
100913401  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X2 [KO:K22517] [EC:2.3.2.27]
100923581  CRKL; crk-like protein [KO:K04438]
116423462  CRK; adapter molecule crk isoform X1 [KO:K04438]
100914252  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X5 [KO:K06277]
100923739  RHOQ; rho-related GTP-binding protein RhoQ [KO:K07194]
100916030  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
100935196  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
100913395  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
100934099  ACACA; acetyl-CoA carboxylase 1 isoform X5 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100932425  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100930790  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
100926799  HK1; hexokinase-1 isoform X4 [KO:K00844] [EC:2.7.1.1]
100919294  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100930478  hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
116421983  HKDC1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
100918168  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
100926139  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
100928944  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100919221  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105750525  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
100918024  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100919530  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100927282  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
100928882  FOXO1; forkhead box protein O1 [KO:K07201]
100931691  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X5 [KO:K07202]
100930187  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
100925165  G6PC2; LOW QUALITY PROTEIN: glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
100916128  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100930321  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
100932503  fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
100932765  fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
100927720  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100933453  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100931480  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100930970  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
100935081  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100930707  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X2 [KO:K04688] [EC:2.7.11.1]
100927485  RPS6; 40S ribosomal protein S6 [KO:K02991]
100918487  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
111718631  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100934653  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
100921545  EIF4E; eukaryotic translation initiation factor 4E isoform X4 [KO:K03259]
100928988  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
100918165  TSC1; hamartin isoform X1 [KO:K07206]
100918445  TSC2; tuberin isoform X1 [KO:K07207]
100919006  RHEB; GTP-binding protein Rheb [KO:K07208]
100923199  BAD; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
100926921  SHC1; SHC-transforming protein 1 isoform X4 [KO:K06279]
100917745  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
100914800  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
100927458  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
100928380  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100931009  SOS1; son of sevenless homolog 1 isoform X2 [KO:K03099]
100932999  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100929168  ras-like protein [KO:K02833]
116419913  HRAS; GTPase HRas [KO:K02833]
100915526  KRAS; GTPase KRas isoform X1 [KO:K07827]
100927252  ras-related protein Rab-26-like [KO:K07827]
100929426  ras protein let-60-like [KO:K07827]
100928986  NRAS; GTPase NRas [KO:K07828]
100913901  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
100934801  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100935202  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
100921899  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
100917396  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
100934330  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100913231  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100931320  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
100917828  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
100914678  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
100917658  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
105750824  suppressor of cytokine signaling 1 [KO:K04694]
100925364  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100934360  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100921040  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
116421513  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
100930815  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100928480  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100924267  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100928932  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
100930081  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
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
shr00010  Glycolysis / Gluconeogenesis
shr00061  Fatty acid biosynthesis
shr00500  Starch and sucrose metabolism
shr04010  MAPK signaling pathway
shr04070  Phosphatidylinositol signaling system
shr04210  Apoptosis
KO pathway
ko04910   
LinkDB

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