IRS1

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Insulin receptor substrate 1
Protein IRS1 PDB 1irs.png
PDB rendering based on 1irs.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols IRS1 ; HIRS-1
External IDs OMIM147545 MGI99454 HomoloGene4049 GeneCards: IRS1 Gene
RNA expression pattern
PBB GE IRS1 204686 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3667 16367
Ensembl ENSG00000169047 ENSMUSG00000055980
UniProt P35568 P35569
RefSeq (mRNA) NM_005544 NM_010570
RefSeq (protein) NP_005535 NP_034700
Location (UCSC) Chr 2:
227.6 – 227.66 Mb
Chr 1:
82.23 – 82.29 Mb
PubMed search [1] [2]

Insulin receptor substrate 1 (IRS-1) is a signalling adapter protein that in humans is encoded by the IRS-1 gene.[1] It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this.

Function[edit]

Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 (IGF-1) receptors to intracellular pathways PI3K / Akt and Erk MAP kinase pathways.

Tyrosine phosphorylation of the insulin receptors or IGF-1 receptors, upon extracellular ligand binding, induces the cytoplasmic binding of IRS-1 to these receptors, through its SH2 domains. Multiple tyrosine residues of IRS-1 itself are then phosphorylated by these receptors. This enables IRS-1 to activate several signalling pathways, including the PI3K pathway and the MAP kinase pathway.

IRS-1 plays important biological function for both metabolic and mitogenic (growth promoting) pathways: mice deficient of IRS1 have only a mild diabetic phenotype, but a pronounced growth impairment, i.e., IRS-1 knockout mice only reach 50% of the weight of normal mice. IRS-1 may also play a role in cancer, as it has been shown that transgenic mice overexpressing IRS-1 develop breast cancer.[2]

Regulation[edit]

The cellular protein levels of IRS-1 are regulated by the Cullin7 E3 ubiquitin ligase, which targets IRS-1 for ubiquitin mediated degradation by the proteasome.[3]

Interactions[edit]

IRS1 has been shown to interact with PTPN11,[4][5] Janus kinase 2,[6][7] Insulin-like growth factor 1 receptor,[8][9][10] Grb2,[11][12][13] PIK3R3,[14][15] Janus kinase 1,[6][16] PTK2,[17] PTPN1,[18][19] MAPK8,[20][21] Bcl-2,[22] Insulin receptor,[20][23] PIK3R1[12][24][25][26] and YWHAE.[27]

References[edit]

  1. ^ Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF (July 1991). "Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein". Nature 352 (6330): 73–7. doi:10.1038/352073a0. PMID 1648180. 
  2. ^ Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, Divisova J, Britton OL, Mohsin S, Allred DC, Hadsell DL, Lee AV (December 2006). "Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2". Molecular and Cellular Biology 26 (24): 9302–14. doi:10.1128/MCB.00260-06. PMC 1698542. PMID 17030631. 
  3. ^ Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Nakajima HO, Field LJ, Wang R, Pan ZQ (May 2008). "The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation". Molecular Cell 30 (4): 403–14. doi:10.1016/j.molcel.2008.03.009. PMC 2633441. PMID 18498745. 
  4. ^ Kuhné, M R; Pawson T; Lienhard G E; Feng G S (June 1993). "The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp". J. Biol. Chem. (UNITED STATES) 268 (16): 11479–81. ISSN 0021-9258. PMID 8505282. 
  5. ^ Myers, M G; Mendez R; Shi P; Pierce J H; Rhoads R; White M F (October 1998). "The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling". J. Biol. Chem. (UNITED STATES) 273 (41): 26908–14. doi:10.1074/jbc.273.41.26908. ISSN 0021-9258. PMID 9756938. 
  6. ^ a b Gual, P; Baron V; Lequoy V; Van Obberghen E (March 1998). "Interaction of Janus kinases JAK-1 and JAK-2 with the insulin receptor and the insulin-like growth factor-1 receptor". Endocrinology (UNITED STATES) 139 (3): 884–93. doi:10.1210/en.139.3.884. ISSN 0013-7227. PMID 9492017. 
  7. ^ Kawazoe, Y; Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S, Kishimoto T (January 2001). "Signal Transducer and Activator of Transcription (Stat)-Induced Stat Inhibitor 1 (Ssi-1)/Suppressor of Cytokine Signaling 1 (Socs1) Inhibits Insulin Signal Transduction Pathway through Modulating Insulin Receptor Substrate 1 (Irs-1) Phosphorylation". J. Exp. Med. (United States) 193 (2): 263–9. doi:10.1084/jem.193.2.263. ISSN 0022-1007. PMC 2193341. PMID 11208867. 
  8. ^ Tartare-Deckert, S; Sawka-Verhelle D, Murdaca J, Van Obberghen E (October 1995). "Evidence for a differential interaction of SHC and the insulin receptor substrate-1 (IRS-1) with the insulin-like growth factor-I (IGF-I) receptor in the yeast two-hybrid system". J. Biol. Chem. (UNITED STATES) 270 (40): 23456–60. doi:10.1074/jbc.270.40.23456. ISSN 0021-9258. PMID 7559507. 
  9. ^ Dey, B R; Frick K; Lopaczynski W; Nissley S P; Furlanetto R W (June 1996). "Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10". Mol. Endocrinol. (UNITED STATES) 10 (6): 631–41. doi:10.1210/me.10.6.631. ISSN 0888-8809. PMID 8776723. 
  10. ^ Mañes, S; Mira E, Gómez-Mouton C, Zhao Z J, Lacalle R A, Martínez-A C (April 1999). "Concerted Activity of Tyrosine Phosphatase SHP-2 and Focal Adhesion Kinase in Regulation of Cell Motility". Mol. Cell. Biol. (UNITED STATES) 19 (4): 3125–35. ISSN 0270-7306. PMC 84106. PMID 10082579. 
  11. ^ Skolnik, E Y; Lee C H; Batzer A; Vicentini L M; Zhou M; Daly R; Myers M J; Backer J M; Ullrich A; White M F (May 1993). "The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling". EMBO J. (ENGLAND) 12 (5): 1929–36. ISSN 0261-4189. PMC 413414. PMID 8491186. 
  12. ^ a b Morrison, Kevin B; Tognon Cristina E; Garnett Mathew J; Deal Cheri; Sorensen Poul H B (August 2002). "ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation". Oncogene (England) 21 (37): 5684–95. doi:10.1038/sj.onc.1205669. ISSN 0950-9232. PMID 12173038. 
  13. ^ Giorgetti-Peraldi, S; Peyrade F; Baron V; Van Obberghen E (December 1995). "Involvement of Janus kinases in the insulin signaling pathway". Eur. J. Biochem. (GERMANY) 234 (2): 656–60. doi:10.1111/j.1432-1033.1995.656_b.x. ISSN 0014-2956. PMID 8536716. 
  14. ^ Xia, X; Serrero G (August 1999). "Multiple forms of p55PIK, a regulatory subunit of phosphoinositide 3-kinase, are generated by alternative initiation of translation". Biochem. J. (ENGLAND) 341 (3): 831–7. doi:10.1042/0264-6021:3410831. ISSN 0264-6021. PMC 1220424. PMID 10417350. 
  15. ^ Mothe, I; Delahaye L; Filloux C; Pons S; White M F; Van Obberghen E (December 1997). "Interaction of wild type and dominant-negative p55PIK regulatory subunit of phosphatidylinositol 3-kinase with insulin-like growth factor-1 signaling proteins". Mol. Endocrinol. (UNITED STATES) 11 (13): 1911–23. doi:10.1210/me.11.13.1911. ISSN 0888-8809. PMID 9415396. 
  16. ^ Johnston, J A; Wang L M, Hanson E P, Sun X J, White M F, Oakes S A, Pierce J H, O'Shea J J (December 1995). "Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases". J. Biol. Chem. (UNITED STATES) 270 (48): 28527–30. doi:10.1074/jbc.270.48.28527. ISSN 0021-9258. PMID 7499365. 
  17. ^ Lebrun, P; Mothe-Satney I, Delahaye L, Van Obberghen E, Baron V (November 1998). "Insulin receptor substrate-1 as a signaling molecule for focal adhesion kinase pp125(FAK) and pp60(src)". J. Biol. Chem. (UNITED STATES) 273 (48): 32244–53. doi:10.1074/jbc.273.48.32244. ISSN 0021-9258. PMID 9822703. 
  18. ^ Goldstein, B J; Bittner-Kowalczyk A, White M F, Harbeck M (February 2000). "Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein". J. Biol. Chem. (UNITED STATES) 275 (6): 4283–9. doi:10.1074/jbc.275.6.4283. ISSN 0021-9258. PMID 10660596. 
  19. ^ Ravichandran, L V; Chen H; Li Y; Quon M J (October 2001). "Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor". Mol. Endocrinol. (United States) 15 (10): 1768–80. doi:10.1210/me.15.10.1768. ISSN 0888-8809. PMID 11579209. 
  20. ^ a b Aguirre, Vincent; Werner Eric D; Giraud Jodel; Lee Yong Hee; Shoelson Steve E; White Morris F (January 2002). "Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action". J. Biol. Chem. (United States) 277 (2): 1531–7. doi:10.1074/jbc.M101521200. ISSN 0021-9258. PMID 11606564. 
  21. ^ Aguirre, V; Uchida T; Yenush L; Davis R; White M F (March 2000). "The c-June NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)". J. Biol. Chem. (UNITED STATES) 275 (12): 9047–54. doi:10.1074/jbc.275.12.9047. ISSN 0021-9258. PMID 10722755. 
  22. ^ Ueno, H; Kondo E, Yamamoto-Honda R, Tobe K, Nakamoto T, Sasaki K, Mitani K, Furusaka A, Tanaka T, Tsujimoto Y, Kadowaki T, Hirai H (February 2000). "Association of Insulin Receptor Substrate Proteins with Bcl-2 and Their Effects on Its Phosphorylation and Antiapoptotic Function". Mol. Biol. Cell (UNITED STATES) 11 (2): 735–46. doi:10.1091/mbc.11.2.735. ISSN 1059-1524. PMC 14806. PMID 10679027. 
  23. ^ Sawka-Verhelle, D; Tartare-Deckert S, White M F, Van Obberghen E (March 1996). "Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786". J. Biol. Chem. (UNITED STATES) 271 (11): 5980–3. doi:10.1074/jbc.271.11.5980. ISSN 0021-9258. PMID 8626379. 
  24. ^ Hadari, Y R; Tzahar E; Nadiv O; Rothenberg P; Roberts C T; LeRoith D; Yarden Y; Zick Y (September 1992). "Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers". J. Biol. Chem. (UNITED STATES) 267 (25): 17483–6. ISSN 0021-9258. PMID 1381348. 
  25. ^ Gual, Philippe; Gonzalez Teresa, Grémeaux Thierry, Barres Romain, Le Marchand-Brustel Yannick, Tanti Jean-François (July 2003). "Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes". J. Biol. Chem. (United States) 278 (29): 26550–7. doi:10.1074/jbc.M212273200. ISSN 0021-9258. PMID 12730242. 
  26. ^ Hamer, I; Foti M, Emkey R, Cordier-Bussat M, Philippe J, De Meyts P, Maeder C, Kahn C R, Carpentier J-L (May 2002). "An arginine to cysteine(252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events". Diabetologia (Germany) 45 (5): 657–67. doi:10.1007/s00125-002-0798-5. ISSN 0012-186X. PMID 12107746. 
  27. ^ Craparo, A; Freund R; Gustafson T A (April 1997). "14-3-3 (epsilon) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner". J. Biol. Chem. (UNITED STATES) 272 (17): 11663–9. doi:10.1074/jbc.272.17.11663. ISSN 0021-9258. PMID 9111084. 

Further reading[edit]

  • Jiang H, Harris MB, Rothman P (2000). "IL-4/IL-13 signaling beyond JAK/STAT". J. Allergy Clin. Immunol. 105 (6 Pt 1): 1063–70. doi:10.1067/mai.2000.107604. PMID 10856136. 
  • Bezerra RM, Chadid TT, Altemani CM, et al. (2004). "Lack of Arg972 polymorphism in the IRS1 gene in Parakanã Brazilian Indians". Hum. Biol. 76 (1): 147–51. doi:10.1353/hub.2004.0015. PMID 15222685. 
  • Gibson SL, Ma Z, Shaw LM (2007). "Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis". Cell Cycle 6 (6): 631–7. doi:10.4161/cc.6.6.3987. PMID 17361103. 
  • Dearth RK, Cui X, Kim HJ, et al. (2007). "Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2". Cell Cycle 6 (6): 705–13. doi:10.4161/cc.6.6.4035. PMID 17374994.