Receptor de insulina

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Receptor de insulina

(PDB:3LOH)
Estruturas disponíveis
PDB Busca de ortólogos: PDBe, RCSB
Identificadores
Símbolos INSR; CD220; HHF5
ID externos OMIM: 147670 MGI96575 HomoloGene20090 ChEMBL: 1981 GeneCards: INSR Gene
Número EC 2.7.10.1
Padrões de expressão do ARN
PBB GE INSR 213792 s at tn.png
Mais dados de expressão
Ortólogos
Espécies Humano Rato
Entrez 3643 16337
Ensembl ENSG00000171105 ENSMUSG00000005534
UniProt P06213 P15208
RefSeq (mRNA) NM_000208.2 NM_010568.2
RefSeq (proteína) NP_000199.2 NP_034698.2
Localização (UCSC) Chr 19:
7.11 – 7.29 Mb
Chr 8:
3.15 – 3.28 Mb
Busca PubMed [1] [2]

O receptor de insulina é um receptor transmembranar que é activado pela insulina, IGF-I, IGF-II, pertencendo à grande classe dos receptores tirosina quinase.[1]

Do ponto de vista metabólico, o receptor de insulina desempenha um papel central na regulação da homeostase da glucose, um processo funcional que quando em condições degeneradas podem resultar numa variedade de manifestações clínicas como a diabetes e o cancro.[2] [3]

Bioquimicamente, o receptor de insulina é codificado por um único gene, INSR, a partir do qual e por splicing alternativo durante a transcrição, resulta nas isoformas IR-A ou IR-B.[4]

Eventos pós-translacionais a jusante, afectando cada uma das isoformas, resulta na formação através de clivagem proteolítica, de subunidades alfa e beta, que após combinação são capazes de homo- ou heterodimerização com vista à produção do receptor transmembranar de insulina.[4]

Interacções[editar | editar código-fonte]

Mostrou-se que o receptor de insulina interage com ectonucleótido pirofosfatase/fosfodiesterase 1,[5] PTPN11,[6] [7] GRB10,[8] [9] [10] [11] [12] GRB7,[13] PRKCD,[14] [15] IRS1,[16] [17] SH2B1[18] [19] e SMAD2 (Mothers against decapentaplegic homolog 2).[20]

Referências

  1. Ward CW, Lawrence MC. (April 2009). "Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor". BioEssays 31 (4): 422–34. DOI:10.1002/bies.200800210. PMID 19274663.
  2. Ebina Y, Ellis L. (April 1985). "The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling.". Cell 40 (4): 747–58. DOI:10.1016/0092-8674(85)90334-4. PMID 2859121.
  3. Malaguarnera R, Belfiore A. (February 2012). "Proinsulin Binds with High Affinity the Insulin Receptor Isoform A and Predominantly Activates the Mitogenic Pathway.". Endocrinology. Epub. DOI:10.1210/en.2011-1843. PMID 22355074.
  4. a b Belfiore A, Frasca F. (Oct 2009). "Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.". Endocr Rev 30 (6): 586–623. DOI:10.1210/er.2008-0047. PMID 19752219.
  5. Maddux, B A; Goldfine I D. (Jan. 2000). "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit". Diabetes 49 (1): 13–9. DOI:10.2337/diabetes.49.1.13. ISSN 0012-1797. PMID 10615944.
  6. Maegawa, H; Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A. (Mar. 1994). "Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro". Biochem. Biophys. Res. Commun. 199 (2): 780–5. DOI:10.1006/bbrc.1994.1297. ISSN 0006-291X. PMID 8135823.
  7. Kharitonenkov, A; Schnekenburger J, Chen Z, Knyazev P, Ali S, Zwick E, White M, Ullrich A. (Dec. 1995). "Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction". J. Biol. Chem. 270 (49): 29189–93. DOI:10.1074/jbc.270.49.29189. ISSN 0021-9258. PMID 7493946.
  8. Langlais, P; Dong L Q, Hu D, Liu F. (Jun. 2000). "Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family". Oncogene 19 (25): 2895–903. DOI:10.1038/sj.onc.1203616. ISSN 0950-9232. PMID 10871840.
  9. Hansen, H; Svensson U, Zhu J, Laviola L, Giorgino F, Wolf G, Smith R J, Riedel H. (Apr. 1996). "Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus". J. Biol. Chem. 271 (15): 8882–6. DOI:10.1074/jbc.271.15.8882. ISSN 0021-9258. PMID 8621530.
  10. Liu, F; Roth R A. (Oct. 1995). "Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function". Proc. Natl. Acad. Sci. U.S.A. 92 (22): 10287–91. DOI:10.1073/pnas.92.22.10287. ISSN 0027-8424. PMID 7479769. Bibcode1995PNAS...9210287L.
  11. He, W; Rose D W, Olefsky J M, Gustafson T A. (Mar. 1998). "Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains". J. Biol. Chem. 273 (12): 6860–7. DOI:10.1074/jbc.273.12.6860. ISSN 0021-9258. PMID 9506989.
  12. Frantz, J D; Giorgetti-Peraldi S, Ottinger E A, Shoelson S E. (Jan. 1997). "Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains". J. Biol. Chem. 272 (5): 2659–67. DOI:10.1074/jbc.272.5.2659. ISSN 0021-9258. PMID 9006901.
  13. Kasus-Jacobi, A; Béréziat V, Perdereau D, Girard J, Burnol A F. (Apr. 2000). "Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2". Oncogene 19 (16): 2052–9. DOI:10.1038/sj.onc.1203469. ISSN 0950-9232. PMID 10803466.
  14. Braiman, L; Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T, Sampson S R. (Apr. 2001). "Insulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscle". Mol. Endocrinol. 15 (4): 565–74. DOI:10.1210/me.15.4.565. ISSN 0888-8809. PMID 11266508.
  15. Rosenzweig, Tovit; Braiman Liora, Bak Asia, Alt Addy, Kuroki Toshio, Sampson Sanford R. (Jun. 2002). "Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling". Diabetes 51 (6): 1921–30. DOI:10.2337/diabetes.51.6.1921. ISSN 0012-1797. PMID 12031982.
  16. Aguirre, Vincent; Werner Eric D, Giraud Jodel, Lee Yong Hee, Shoelson Steve E, White Morris F. (Jan. 2002). "Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action". J. Biol. Chem. 277 (2): 1531–7. DOI:10.1074/jbc.M101521200. ISSN 0021-9258. PMID 11606564.
  17. Sawka-Verhelle, D; Tartare-Deckert S, White M F, Van Obberghen E. (Mar. 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. 271 (11): 5980–3. DOI:10.1074/jbc.271.11.5980. ISSN 0021-9258. PMID 8626379.
  18. Kotani, K; Wilden P, Pillay T S. (Oct. 1998). "SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase". Biochem. J. 335 (1): 103–9. ISSN 0264-6021. PMID 9742218.
  19. Nelms, K; O'Neill T J, Li S, Hubbard S R, Gustafson T A, Paul W E. (Dec. 1999). "Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain". Mamm. Genome 10 (12): 1160–7. DOI:10.1007/s003359901183. ISSN 0938-8990. PMID 10594240.
  20. O'Neill, T J; Zhu Y, Gustafson T A. (Apr. 1997). "Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation". J. Biol. Chem. 272 (15): 10035–40. DOI:10.1074/jbc.272.15.10035. ISSN 0021-9258. PMID 9092546.

Leitura adicional[editar | editar código-fonte]

  • Pearson RB, Kemp BE. (1991). "Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations". Meth. Enzymol. 200: 62–81. DOI:10.1016/0076-6879(91)00127-I. PMID 1956339.
  • Joost HG. (1995). "Structural and functional heterogeneity of insulin receptors". Cell. Signal. 7 (2): 85–91. DOI:10.1016/0898-6568(94)00071-I. PMID 7794689.
  • O'Dell SD, Day IN. (1998). "Insulin-like growth factor II (IGF-II)". Int. J. Biochem. Cell Biol. 30 (7): 767–71. DOI:10.1016/S1357-2725(98)00048-X. PMID 9722981.
  • Lopaczynski W. (1999). "Differential regulation of signaling pathways for insulin and insulin-like growth factor I". Acta Biochim. Pol. 46 (1): 51–60. PMID 10453981.
  • Sasaoka T, Kobayashi M. (2000). "The functional significance of Shc in insulin signaling as a substrate of the insulin receptor". Endocr. J. 47 (4): 373–81. DOI:10.1507/endocrj.47.373. PMID 11075717.
  • Perz M, Torlińska T. (2001). "Insulin receptor—structural and functional characteristics". Med. Sci. Monit. 7 (1): 169–77. PMID 11208515.
  • Benaim G, Villalobo A. (2002). "Phosphorylation of calmodulin. Functional implications". Eur. J. Biochem. 269 (15): 3619–31. DOI:10.1046/j.1432-1033.2002.03038.x. PMID 12153558.