Factor de crecemento de fibroblastos ácido
O factor de crecemento de fibroblastos ácido (aFGF), tamén chamado FGF1 ou FGF-α é un factor de crecemento e proteína de sinalización codificado polo xene FGF1 do cromosoma 5 humano.[1][2] É sintetizado como un polipéptido de 155 aminoácidos, cuxa forma madura é unha proteína non glicosilada de 17-18 kDa. A proteína factor de crecemento de fibroblastos foi purificada primeiramente en 1975, pero pouco despois, usando diferentes condicións, illáronse o FGF ácido, o factor de crecemento de heparina 1 e o factor de crecemento endotelial-1.[3] A secuenciación dos xenes revelou que o FGF1 era un membro da familia de FGF de proteínas.
O FGF1 non ten unha secuencia sinal clara, polo que non é segregada a través das vías clásicas, pero non parece formar un dímero ligado por ponte disulfuro dentro das células, que se asocia cun complexo de proteínas na membrana plasmática (incluíndo S100A13 e Syt1) que despois axudan a pasala a través da membrana ata o exterior da célula.[4][5] Unha vez que está nas condicións redutoras dos tecidos circundantes, o dímero disóciase formando o FGF1 monómero que pode entrar na circulación sistémica ou ser secuestrado nos tecidos uníndose a proteoglicanos de heparán sulfato da matriz extracelular. O FGF1 pode despois unirse e exercer os seus efectos por medio de proteínas específicas receptoras do factor de crecemento de fibroblastos (FGFR), as cales constitúen unha familia de moléculas estreitamente relacionadas.[6]
Ademais da súa actividade extracelular, o FGF1 pode tamén funcionar intracelularmente. A proteína ten unha secuencia de localización nuclear (NLS), pero a ruta que segue o FGF1 para chegar ao núcleo non está clara e parece que cómpre que se una a algún tipo de receptor da superficie celular, seguido da súa internalización e translocación ao núcleo, onde pode interaccionar con isoformas nucleares de FGFR.[6] Isto é diferente do que ocorre co FGF2, que tamén pode activar os FGFR nucleares, pero que ten variantes de empalme da proteína que nunca abandonan a célula e van directamente ao núcleo.
Función[editar | editar a fonte]
Os membros da familia do FGF posúen amplas actividades mitoxénicas e de supervivencia celular e están implicados en diversos procesos biolóxicos, como o desenvolvemento embrionario, crecemento celular, morfoxénese, reparación de tecidos e o crecemento e invasión tumorais. Esta proteína funciona como un modificador da migración e proliferación de células endoteliais, así como un factor anxioxénico. Actúa como mitóxeno para diversas células derivadas do mesoderma e neuroectoderma in vitro, así se pensa que está implicado na organoxénese. Describíronse tres variantes de empalme alternativo que codifican diferentes isoformas.[7]
O FGF1 é multifuncional e ten moitos efectos. Como exemplo, en ratos con diabetes inducida pola dieta, que é un equivalente experimental da diabetes de tipo 2 humana, unha soa inxección da proteína FGF1 é dabondo para restablecer os niveis de azucre do sangue ata uns valores saudables durante máis de dous días.[8]
Interaccións[editar | editar a fonte]
O FGF1 presenta interaccións con:
- CSNK2A2[9]
- CSNK2B[9]
- CSNK2A1[9]
- FIBP[10]
- FGFR1[11][12]
- FGFR2[12][13][14]
- FGFR3[12][15]
- FGFR4[16][17]
- HSPA9[18]
- S100A13[5][19][20] e
- Sinaptotagmina 1 (SYT1) [5][19]
Notas[editar | editar a fonte]
- ↑ Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J (September 1990). "Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors". The EMBO Journal 9 (9): 2685–92. PMC 551973. PMID 1697263.
- ↑ Jaye M, Howk R, Burgess W, Ricca GA, Chiu IM, Ravera MW, O'Brien SJ, Modi WS, Maciag T, Drohan WN (August 1986). "Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization". Science 233 (4763): 541–5. PMID 3523756. doi:10.1126/science.3523756.
- ↑ Burgess WH, Maciag T (1989). "The heparin-binding (fibroblast) growth factor family of proteins". Annual Review of Biochemistry 58: 575–606. PMID 2549857. doi:10.1146/annurev.bi.58.070189.003043.
- ↑ Tarantini F, Gamble S, Jackson A, Maciag T (December 1995). "The cysteine residue responsible for the release of fibroblast growth factor-1 residues in a domain independent of the domain for phosphatidylserine binding". The Journal of Biological Chemistry 270 (49): 29039–42. PMID 7493920. doi:10.1074/jbc.270.49.29039.
- ↑ 5,0 5,1 5,2 Prudovsky I, Bagala C, Tarantini F, Mandinova A, Soldi R, Bellum S, Maciag T (July 2002). "The intracellular translocation of the components of the fibroblast growth factor 1 release complex precedes their assembly prior to export". The Journal of Cell Biology 158 (2): 201–8. PMC 2173119. PMID 12135982. doi:10.1083/jcb.200203084.
- ↑ 6,0 6,1 Coleman SJ, Bruce C, Chioni AM, Kocher HM, Grose RP (August 2014). "The ins and outs of fibroblast growth factor receptor signalling". Clinical Science 127 (4): 217–31. PMID 24780002. doi:10.1042/CS20140100.
- ↑ "Entrez Gene: FGF1 fibroblast growth factor 1 (acidic)".
- ↑ Suh JM, Jonker JW, Ahmadian M, Goetz R, Lackey D, Osborn O, Huang Z, Liu W, Yoshihara E, van Dijk TH, Havinga R, Fan W, Yin YQ, Yu RT, Liddle C, Atkins AR, Olefsky JM, Mohammadi M, Downes M, Evans RM (September 2014). "Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer". Nature 513 (7518): 436–9. PMC 4184286. PMID 25043058. doi:10.1038/nature13540. Resumo divulgativo – Salk Institute.
- ↑ 9,0 9,1 9,2 Skjerpen CS, Nilsen T, Wesche J, Olsnes S (August 2002). "Binding of FGF-1 variants to protein kinase CK2 correlates with mitogenicity". The EMBO Journal 21 (15): 4058–69. PMC 126148. PMID 12145206. doi:10.1093/emboj/cdf402.
- ↑ Kolpakova E, Wiedłocha A, Stenmark H, Klingenberg O, Falnes PO, Olsnes S (November 1998). "Cloning of an intracellular protein that binds selectively to mitogenic acidic fibroblast growth factor". The Biochemical Journal. 336 ( Pt 1) (1): 213–22. PMC 1219860. PMID 9806903. doi:10.1042/bj3360213.
- ↑ Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M (September 2000). "Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization". Molecular Cell 6 (3): 743–50. PMID 11030354. doi:10.1016/s1097-2765(00)00073-3.
- ↑ 12,0 12,1 12,2 Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM (January 1996). "Expression and biological activity of mouse fibroblast growth factor-9". The Journal of Biological Chemistry 271 (3): 1726–31. PMID 8576175. doi:10.1074/jbc.271.3.1726.
- ↑ Stauber DJ, DiGabriele AD, Hendrickson WA (January 2000). "Structural interactions of fibroblast growth factor receptor with its ligands". Proceedings of the National Academy of Sciences of the United States of America 97 (1): 49–54. PMC 26614. PMID 10618369. doi:10.1073/pnas.97.1.49.
- ↑ Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL (October 2000). "Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin". Nature 407 (6807): 1029–34. PMID 11069186. doi:10.1038/35039551.
- ↑ Chellaiah A, Yuan W, Chellaiah M, Ornitz DM (December 1999). "Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity". The Journal of Biological Chemistry 274 (49): 34785–94. PMID 10574949. doi:10.1074/jbc.274.49.34785.
- ↑ Loo BB, Darwish KK, Vainikka SS, Saarikettu JJ, Vihko PP, Hermonen JJ, Goldman AA, Alitalo KK, Jalkanen MM (May 2000). "Production and characterization of the extracellular domain of recombinant human fibroblast growth factor receptor 4". The International Journal of Biochemistry & Cell Biology 32 (5): 489–97. PMID 10736564. doi:10.1016/S1357-2725(99)00145-4.
- ↑ Kan M, Wu X, Wang F, McKeehan WL (May 1999). "Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase". The Journal of Biological Chemistry 274 (22): 15947–52. PMID 10336501. doi:10.1074/jbc.274.22.15947.
- ↑ Mizukoshi E, Suzuki M, Loupatov A, Uruno T, Hayashi H, Misono T, Kaul SC, Wadhwa R, Imamura T (October 1999). "Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin". The Biochemical Journal. 343 Pt 2 (2): 461–6. PMC 1220575. PMID 10510314. doi:10.1042/0264-6021:3430461.
- ↑ 19,0 19,1 Mouta Carreira C, LaVallee TM, Tarantini F, Jackson A, Lathrop JT, Hampton B, Burgess WH, Maciag T (August 1998). "S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro". The Journal of Biological Chemistry 273 (35): 22224–31. PMID 9712836. doi:10.1074/jbc.273.35.22224.
- ↑ Landriscina M, Bagalá C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T (July 2001). "Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress". The Journal of Biological Chemistry 276 (27): 25549–57. PMID 11432880. doi:10.1074/jbc.M102925200.
Véxase tamén[editar | editar a fonte]
Outros artigos[editar | editar a fonte]
Bibliografía[editar | editar a fonte]
- Yu YL, Kha H, Golden JA, Migchielsen AA, Goetzl EJ, Turck CW (April 1992). "An acidic fibroblast growth factor protein generated by alternate splicing acts like an antagonist". The Journal of Experimental Medicine 175 (4): 1073–80. PMC 2119192. PMID 1372643. doi:10.1084/jem.175.4.1073.
- Chiu IM, Wang WP, Lehtoma K (May 1990). "Alternative splicing generates two forms of mRNA coding for human heparin-binding growth factor 1". Oncogene 5 (5): 755–62. PMID 1693186.
- Zhu X, Komiya H, Chirino A, Faham S, Fox GM, Arakawa T, Hsu BT, Rees DC (January 1991). "Three-dimensional structures of acidic and basic fibroblast growth factors". Science 251 (4989): 90–3. PMID 1702556. doi:10.1126/science.1702556.
- Wang WP, Quick D, Balcerzak SP, Needleman SW, Chiu IM (September 1991). "Cloning and sequence analysis of the human acidic fibroblast growth factor gene and its preservation in leukemia patients". Oncogene 6 (9): 1521–9. PMID 1717925.
- Wu DQ, Kan MK, Sato GH, Okamoto T, Sato JD (September 1991). "Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors". The Journal of Biological Chemistry 266 (25): 16778–85. PMID 1885605.
- Crumley G, Dionne CA, Jaye M (August 1990). "The gene for human acidic fibroblast growth factor encodes two upstream exons alternatively spliced to the first coding exon". Biochemical and Biophysical Research Communications 171 (1): 7–13. PMID 2393407. doi:10.1016/0006-291X(90)91348-V.
- Harper JW, Strydom DJ, Lobb RR (July 1986). "Human class 1 heparin-binding growth factor: structure and homology to bovine acidic brain fibroblast growth factor". Biochemistry 25 (14): 4097–103. PMID 2427112. doi:10.1021/bi00362a017.
- Winkles JA, Friesel R, Burgess WH, Howk R, Mehlman T, Weinstein R, Maciag T (October 1987). "Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor)". Proceedings of the National Academy of Sciences of the United States of America 84 (20): 7124–8. PMC 299242. PMID 2444975. doi:10.1073/pnas.84.20.7124.
- Wang WP, Lehtoma K, Varban ML, Krishnan I, Chiu IM (June 1989). "Cloning of the gene coding for human class 1 heparin-binding growth factor and its expression in fetal tissues". Molecular and Cellular Biology 9 (6): 2387–95. PMC 362312. PMID 2474753.
- Mergia A, Tischer E, Graves D, Tumolo A, Miller J, Gospodarowicz D, Abraham JA, Shipley GD, Fiddes JC (November 1989). "Structural analysis of the gene for human acidic fibroblast growth factor". Biochemical and Biophysical Research Communications 164 (3): 1121–9. PMID 2590193. doi:10.1016/0006-291X(89)91785-3.
- Gimenez-Gallego G, Conn G, Hatcher VB, Thomas KA (July 1986). "The complete amino acid sequence of human brain-derived acidic fibroblast growth factor". Biochemical and Biophysical Research Communications 138 (2): 611–7. PMID 3527167. doi:10.1016/S0006-291X(86)80540-X.
- Gautschi P, Fràter-Schröder M, Böhlen P (August 1986). "Partial molecular characterization of endothelial cell mitogens from human brain: acidic and basic fibroblast growth factors". FEBS Letters 204 (2): 203–7. PMID 3732516. doi:10.1016/0014-5793(86)80812-2.
- Gautschi-Sova P, Müller T, Böhlen P (November 1986). "Amino acid sequence of human acidic fibroblast growth factor". Biochemical and Biophysical Research Communications 140 (3): 874–80. PMID 3778488. doi:10.1016/0006-291X(86)90716-3.
- Gimenez-Gallego G, Conn G, Hatcher VB, Thomas KA (March 1986). "Human brain-derived acidic and basic fibroblast growth factors: amino terminal sequences and specific mitogenic activities". Biochemical and Biophysical Research Communications 135 (2): 541–8. PMID 3964259. doi:10.1016/0006-291X(86)90028-8.
- Zhao XM, Yeoh TK, Hiebert M, Frist WH, Miller GG (November 1993). "The expression of acidic fibroblast growth factor (heparin-binding growth factor-1) and cytokine genes in human cardiac allografts and T cells". Transplantation 56 (5): 1177–82. PMID 7504343. doi:10.1097/00007890-199311000-00025.
- Pineda-Lucena A, Jiménez MA, Nieto JL, Santoro J, Rico M, Giménez-Gallego G (September 1994). "1H-NMR assignment and solution structure of human acidic fibroblast growth factor activated by inositol hexasulfate". Journal of Molecular Biology 242 (1): 81–98. PMID 7521397. doi:10.1006/jmbi.1994.1558.
- Chotani MA, Payson RA, Winkles JA, Chiu IM (February 1995). "Human fibroblast growth factor 1 gene expression in vascular smooth muscle cells is modulated via an alternate promoter in response to serum and phorbol ester". Nucleic Acids Research 23 (3): 434–41. PMC 306694. PMID 7533902. doi:10.1093/nar/23.3.434.
- Opalenik SR, Shin JT, Wehby JN, Mahesh VK, Thompson JA (July 1995). "The HIV-1 TAT protein induces the expression and extracellular appearance of acidic fibroblast growth factor". The Journal of Biological Chemistry 270 (29): 17457–67. PMID 7542239. doi:10.1074/jbc.270.29.17457.
- Myers RL, Payson RA, Chotani MA, Deaven LL, Chiu IM (February 1993). "Gene structure and differential expression of acidic fibroblast growth factor mRNA: identification and distribution of four different transcripts". Oncogene 8 (2): 341–9. PMID 7678925.
