KEGG   PATHWAY: etl04910
Entry
etl04910                    Pathway                                
Name
Insulin signaling pathway - Empidonax traillii (willow flycatcher)
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
etl04910  Insulin signaling pathway
etl04910

Organism
Empidonax traillii (willow flycatcher) [GN:etl]
Gene
114059852  INS; insulin isoform X1 [KO:K04526]
114069501  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
114068746  IRS1; insulin receptor substrate 1 [KO:K16172]
114059692  IRS4; insulin receptor substrate 4 [KO:K07187]
114073373  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
114056772  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
114062212  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
114069500  phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
114057709  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
114056876  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
114062399  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
114061437  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
114066717  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114059171  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114055112  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
114068604  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
114055006  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
114063365  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
114064849  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
114065742  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
114056438  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
114061846  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
114061382  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
114066434  protein phosphatase 1 regulatory subunit 3C-B-like [KO:K07189]
114056079  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
114060505  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
114067424  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
114067883  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
114068296  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform [KO:K07190]
114058208  CALM1; calmodulin-1 [KO:K02183]
114065085  CALML4; calmodulin-like protein 4 [KO:K02183]
114070213  calmodulin, striated muscle [KO:K02183]
114064855  CALM2; calmodulin-2 [KO:K02183]
114069687  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
114066752  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
114070370  glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
114060399  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
114064916  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
114060699  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
114056796  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
114054751  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
114060554  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit [KO:K04739]
114063173  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
114061183  PRKCI; protein kinase C iota type isoform X1 [KO:K06069] [EC:2.7.11.13]
114071965  solute carrier family 2, facilitated glucose transporter member 4-like [KO:K07191]
114061256  FLOT2; flotillin-2 [KO:K07192]
114056702  SH2B2; SH2B adapter protein 2 [KO:K07193]
114065365  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
114067820  CBL; E3 ubiquitin-protein ligase CBL [KO:K04707] [EC:2.3.2.27]
114057223  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
114060458  CRK; adapter molecule crk isoform X1 [KO:K04438]
114061504  CRKL; crk-like protein isoform X1 [KO:K04438]
114073801  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
114067531  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
114070244  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
114065971  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
114057474  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
114062660  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
114060364  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
114071203  hexokinase-2-like [KO:K00844] [EC:2.7.1.1]
114072590  hexokinase-2-like [KO:K00844] [EC:2.7.1.1]
114066290  putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
114066291  hexokinase-1 [KO:K00844] [EC:2.7.1.1]
114063836  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
114071694  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
114063712  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
114055190  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
114068623  5'-AMP-activated protein kinase catalytic subunit alpha-1-like [KO:K07198] [EC:2.7.11.31]
114063939  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
114056606  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
114062395  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
114055316  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
114071070  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
114059362  FOXO1; forkhead box protein O1 [KO:K07201]
114057281  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
114069040  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
114063657  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
114073752  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
114056026  fructose-1,6-bisphosphatase isozyme 2 isoform X1 [KO:K03841] [EC:3.1.3.11]
114056034  fructose-1,6-bisphosphatase 1-like [KO:K03841] [EC:3.1.3.11]
114056225  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
114056898  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
114068210  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
114067697  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
114063332  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
114056556  RPS6; 40S ribosomal protein S6 [KO:K02991]
114066482  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 isoform X1 [KO:K07205]
114060793  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
114066890  eukaryotic translation initiation factor 4E [KO:K03259]
114063842  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
114073788  TSC1; hamartin isoform X1 [KO:K07206]
114064312  TSC2; tuberin isoform X1 [KO:K07207]
114062390  RHEB; GTP-binding protein Rheb isoform X1 [KO:K07208]
114068431  SHC1; SHC-transforming protein 1 [KO:K06279]
114066416  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
114061143  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
114059944  SHC4; SHC-transforming protein 4 [KO:K17449]
114063378  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
114060067  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
114070305  SOS2; son of sevenless homolog 2 [KO:K03099]
114064818  HRAS; GTPase HRas [KO:K02833]
114068618  KRAS; GTPase KRas isoform X1 [KO:K07827]
114064402  NRAS; GTPase NRas [KO:K07828]
114056183  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
114059216  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
114055284  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
114068839  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
114061800  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
114070715  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
114062338  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
114058470  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
114062240  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
114060367  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
114069886  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
114067269  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
114066016  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
114059149  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
114054718  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
114065198  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
114066442  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
114059614  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 [KO:K15909] [EC:3.1.3.86]
114065162  phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2-like [KO:K15909] [EC:3.1.3.86]
114067417  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase [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
etl00010  Glycolysis / Gluconeogenesis
etl00061  Fatty acid biosynthesis
etl00500  Starch and sucrose metabolism
etl04010  MAPK signaling pathway
etl04070  Phosphatidylinositol signaling system
etl04210  Apoptosis
KO pathway
ko04910   
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