KEGG   PATHWAY: nss04910
Entry
nss04910                    Pathway                                
Name
Insulin signaling pathway - Notechis scutatus (mainland tiger snake)
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
nss04910  Insulin signaling pathway
nss04910

Organism
Notechis scutatus (mainland tiger snake) [GN:nss]
Gene
113409751  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
113409774  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
113409938  IRS1; LOW QUALITY PROTEIN: insulin receptor substrate 1 [KO:K16172]
113410372  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
113410416  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
113410828  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
113410866  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
113410870  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
113410894  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
113410934  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
113410978  [KO:K02649]
113410991  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
113411332  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
113411398  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
113411541  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
113411953  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
113411977  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
113412014  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
113412064  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
113412092  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
113412472  INS; insulin [KO:K04526]
113412507  HRAS; GTPase HRas [KO:K02833]
113412584  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
113412765  FOXO1; forkhead box protein O1 [KO:K07201]
113413278  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113413432  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
113413668  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
113413735  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
113413935  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
113414033  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [KO:K01106] [EC:3.1.3.56]
113414062  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
113414090  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
113414124  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
113414133  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
113414184  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
113414290  SHC3; SHC-transforming protein 3 [KO:K17448]
113414444  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
113414477  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
113414686  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
113414934  [KO:K07189]
113415134  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
113415323  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
113415391  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
113415418  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
113415419  [KO:K00844] [EC:2.7.1.1]
113415479  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
113415615  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
113415711  HK3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
113415721  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
113416564  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
113416615  IRS4; insulin receptor substrate 4 [KO:K07187]
113416842  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
113416978  NRAS; GTPase NRas [KO:K07828]
113417236  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
113417531  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
113417677  PPP1R3F; protein phosphatase 1 regulatory subunit 3F [KO:K17453]
113417793  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
113418177  [KO:K04345] [EC:2.7.11.11]
113418209  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
113418294  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
113418412  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
113418517  [KO:K04696]
113418546  [KO:K07827]
113418552  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
113419053  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
113419054  KRAS; GTPase KRas isoform X1 [KO:K07827]
113419166  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
113419435  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
113419440  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
113419521  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
113419522  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
113419573  IRS2; insulin receptor substrate 2 [KO:K07187]
113419661  CALM1; calmodulin-1 [KO:K02183]
113419930  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
113420208  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
113420311  SOS1; son of sevenless homolog 1 [KO:K03099]
113420388  RPS6; 40S ribosomal protein S6 [KO:K02991]
113420520  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
113420936  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
113421163  CBLC; E3 ubiquitin-protein ligase CBL-C [KO:K04707] [EC:2.3.2.27]
113421205  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
113421297  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
113421301  CALML6; calmodulin-like protein 6 [KO:K02183]
113421356  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
113421446  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
113421719  [KO:K04438]
113421727  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
113421765  [KO:K04371] [EC:2.7.11.24]
113421995  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
113422060  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
113422144  CRKL; crk-like protein [KO:K04438]
113422282  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
113422287  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
113422410  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
113422560  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
113422575  TSC2; tuberin [KO:K07207]
113422608  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
113422611  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
113422669  CALM2; calmodulin-2 [KO:K02183]
113422968  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
113423088  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
113423133  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
113423184  FLOT1; LOW QUALITY PROTEIN: flotillin-1 [KO:K07192]
113423238  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
113423283  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
113423385  [KO:K00844] [EC:2.7.1.1]
113423625  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
113423907  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
113424365  [KO:K00688] [EC:2.4.1.1]
113424609  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
113424646  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
113424757  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
113424903  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
113425094  SHC2; SHC-transforming protein 2 [KO:K17447]
113425248  TSC1; hamartin isoform X1 [KO:K07206]
113425479  [KO:K01084] [EC:3.1.3.9]
113425484  [KO:K01084] [EC:3.1.3.9]
113425513  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
113425569  [KO:K04456] [EC:2.7.11.1]
113425679  CALML4; calmodulin-like protein 4 [KO:K02183]
113425728  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
113425962  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
113426188  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
113426328  [KO:K02183]
113426559  CRK; adapter molecule crk [KO:K04438]
113427675  IKBKB; LOW QUALITY PROTEIN: inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
113428711  [KO:K01596] [EC:4.1.1.32]
113428712  [KO:K01596] [EC:4.1.1.32]
113428857  [KO:K07191]
113429403  FLOT2; flotillin-2 [KO:K07192]
113429826  BAD; bcl2-associated agonist of cell death [KO:K02158]
113430912  [KO:K02183]
113431490  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
113432841  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
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
nss00010  Glycolysis / Gluconeogenesis
nss00061  Fatty acid biosynthesis
nss00500  Starch and sucrose metabolism
nss04010  MAPK signaling pathway
nss04070  Phosphatidylinositol signaling system
nss04210  Apoptosis
KO pathway
ko04910   

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