KEGG   PATHWAY: tfn04910
Entry
tfn04910                    Pathway                                
Name
Insulin signaling pathway - Trachypithecus francoisi (Francois's langur)
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
tfn04910  Insulin signaling pathway
tfn04910

Organism
Trachypithecus francoisi (Francois's langur) [GN:tfn]
Gene
117081143  INS; insulin [KO:K04526]
117076717  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
117094439  IRS1; LOW QUALITY PROTEIN: insulin receptor substrate 1 [KO:K16172]
117063516  IRS2; insulin receptor substrate 2 [KO:K07187]
117077563  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
117065206  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
117092662  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
117075022  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
117083761  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
117084122  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
117093348  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
117083793  LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1-like [KO:K06276] [EC:2.7.11.1]
117071286  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117091956  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
117076331  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
117083458  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
117090404  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
117091538  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
117080254  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
117089406  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
117062530  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
117095609  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
117069020  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
117069970  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
117063034  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
117072910  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
117091627  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
117083968  PPP1R3F; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3F [KO:K17453]
117087666  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
117073532  phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
117083595  phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform isoform X1 [KO:K00871] [EC:2.7.11.19]
117078452  PHKA2; LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, liver isoform [KO:K07190]
117087742  PHKB; phosphorylase b kinase regulatory subunit beta isoform X1 [KO:K07190]
117077363  LOW QUALITY PROTEIN: phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform-like [KO:K07190]
117069878  calmodulin-1-like [KO:K02183]
117079553  calmodulin-1-like [KO:K02183]
117070455  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
117070827  calmodulin-1 [KO:K02183]
117062348  CALM2; calmodulin-2 [KO:K02183]
117071553  CALM1; calmodulin-1 [KO:K02183]
117091446  CALM3; calmodulin-3 [KO:K02183]
117082197  CALML3; calmodulin-like protein 3 [KO:K02183]
117082198  CALML5; calmodulin-like protein 5 [KO:K02183]
117093967  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
117095064  calmodulin-1-like [KO:K02183]
117069659  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
117081421  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
117068347  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
117081551  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
117098498  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
117092158  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
117074523  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
117081006  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit isoform X1 [KO:K04739]
117073585  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
117073755  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
117067379  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit isoform X1 [KO:K04739]
117075239  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
117093432  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
117083715  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
117067797  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
117088386  FLOT1; flotillin-1 isoform X1 [KO:K07192]
117066453  FLOT2; flotillin-2 isoform X1 [KO:K07192]
117072409  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
117069530  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
117081759  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
117083570  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
117096632  CRKL; crk-like protein [KO:K04438]
117067958  CRK; adapter molecule crk isoform X1 [KO:K04438]
117073498  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
117062359  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
117080864  LOW QUALITY PROTEIN: rho-related GTP-binding protein RhoQ-like [KO:K07194]
117066712  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
117075826  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
117074757  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
117067361  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
117089443  ACACB; LOW QUALITY PROTEIN: acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
117066371  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
117074608  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
117062074  HK2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
117099756  hexokinase-1-like [KO:K00844] [EC:2.7.1.1]
117065352  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
117082732  HKDC1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
117082733  HK1; hexokinase-1 isoform X1 [KO:K00844] [EC:2.7.1.1]
117073299  GCK; hexokinase-4 [KO:K12407] [EC:2.7.1.2]
117091972  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
117065053  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
117089314  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
117075492  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
117090183  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
117073087  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
117094511  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
117097036  FOXO1; forkhead box protein O1 isoform X1 [KO:K07201]
117085214  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
117066897  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
117066932  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
117094898  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
117062703  FBP1; fructose-1,6-bisphosphatase 1 isoform X1 [KO:K03841] [EC:3.1.3.11]
117062718  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
117068976  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
117069918  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
117093322  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
117066804  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
117080241  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
117067326  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
117096550  40S ribosomal protein S6-like [KO:K02991]
117098620  RPS6; 40S ribosomal protein S6 [KO:K02991]
117063728  40S ribosomal protein S6-like [KO:K02991]
117082680  40S ribosomal protein S6-like [KO:K02991]
117065200  40S ribosomal protein S6-like [KO:K02991]
117092123  40S ribosomal protein S6-like [KO:K02991]
117084893  40S ribosomal protein S6-like [KO:K02991]
117094781  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
117077273  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E-binding protein 1-like [KO:K07205]
117081994  eukaryotic translation initiation factor 4E [KO:K03259]
117064531  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
117082166  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
117084670  eukaryotic translation initiation factor 4E type 2 [KO:K03259]
117085700  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
117086832  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
117073735  TSC1; hamartin isoform X1 [KO:K07206]
117097810  TSC2; tuberin isoform X1 [KO:K07207]
117073572  RHEB; GTP-binding protein Rheb [KO:K07208]
117080612  BAD; bcl2-associated agonist of cell death [KO:K02158]
117075160  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
117074894  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
117098366  SHC3; SHC-transforming protein 3 [KO:K17448]
117070688  SHC4; SHC-transforming protein 4 [KO:K17449]
117066678  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
117069667  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
117062427  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
117081688  HRAS; GTPase HRas isoform X1 [KO:K02833]
117074634  NRAS; GTPase NRas [KO:K07828]
117078298  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
117072297  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
117083269  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
117084479  LOW QUALITY PROTEIN: RAF proto-oncogene serine/threonine-protein kinase-like [KO:K04366] [EC:2.7.11.1]
117070473  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
117076490  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
117087606  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
117096627  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
117092651  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
117076573  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
117078321  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
117080423  ETS domain-containing protein Elk-1-like [KO:K04375]
117097650  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
117089622  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
117066771  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
117069613  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
117068920  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
117092722  PTPRF; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
117082864  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
117065429  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
117085362  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
117095630  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
117081792  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
117082515  INPP5A; inositol polyphosphate-5-phosphatase A isoform X1 [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
tfn00010  Glycolysis / Gluconeogenesis
tfn00061  Fatty acid biosynthesis
tfn00500  Starch and sucrose metabolism
tfn04010  MAPK signaling pathway
tfn04070  Phosphatidylinositol signaling system
tfn04210  Apoptosis
KO pathway
ko04910   
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