Fibroblast growth factor 1 explained

Fibroblast growth factor 1 (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene.^{[1] [2]} It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1.^[3] Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.

FGF-1 has no definitive signal sequence and thus is not secreted through classical pathways, but it does appear to form a disulfide linked dimer inside cells that associate with a complex of proteins at the cell membrane (including S100A13 and Syt1) which then help flip it through the membrane to the exterior of the cell.^{[4] [5]} Once in the reducing conditions of the surrounding tissue, the dimer dissociates into monomeric FGF1 that can enter systemic circulation or be sequestered in tissues binding to heparan sulfate proteoglycans of the extracellular matrix. FGF1 can then bind to and exert its effects via specific fibroblast growth factor receptor (FGFR) proteins which themselves constitute a family of closely related molecules.^[6]

In addition to its extracellular activity, FGF1 can also function intracellularly. The protein has a nuclear localization sequence (NLS) but the route that FGF1 takes to get to the nucleus is unclear and it appears that some sort of cell surface receptor binding is necessary, followed by its internalization and translocation to the nucleus whereupon it can interact with nuclear isoforms of FGFRs. This is different from FGF2 which also can activate nuclear FGFRs but has splicing variants of the protein that never leave the cell and go directly to the nucleus.

Function

FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein functions as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor. It acts as a mitogen for a variety of mesoderm- and neuroectoderm-derived cells in vitro, thus is thought to be involved in organogenesis. Three alternatively spliced variants encoding different isoforms have been described.^[7]

FGF1 is multifunctional with many reported effects. For one example, in mice with diet-induced diabetes that is an experimental equivalent of type 2 diabetes in humans, a single injection of the FGF1 protein is enough to restore blood sugar levels to a healthy range for > 2 days.^[8]

Interactions

FGF1 has been shown to interact with:

• • CSNK2A2 CSNK2B^[9]
• CSNK2A1^[9]
• FIBP^[10]
• FGFR1^{[11] [12]}
• FGFR2^{[12] [13] [14]}
• FGFR3^{[12] [15]}
• FGFR4^{[16] [17]}
• HSPA9^[18] and
• S100A13^{[19] [20]}
• Synaptotagmin 1 (SYT1)

See also

• Fibroblast growth factor

Further reading

• Yu YL, Kha H, Golden JA, Migchielsen AA, Goetzl EJ, Turck CW . An acidic fibroblast growth factor protein generated by alternate splicing acts like an antagonist . The Journal of Experimental Medicine . 175 . 4 . 1073–80 . April 1992 . 1372643 . 2119192 . 10.1084/jem.175.4.1073 .
• Chiu IM, Wang WP, Lehtoma K . Alternative splicing generates two forms of mRNA coding for human heparin-binding growth factor 1 . Oncogene . 5 . 5 . 755–62 . May 1990 . 1693186 .
• Zhu X, Komiya H, Chirino A, Faham S, Fox GM, Arakawa T, Hsu BT, Rees DC . Three-dimensional structures of acidic and basic fibroblast growth factors . Science . 251 . 4989 . 90–3 . January 1991 . 1702556 . 10.1126/science.1702556 . 1991Sci...251...90Z .
• Wang WP, Quick D, Balcerzak SP, Needleman SW, Chiu IM . Cloning and sequence analysis of the human acidic fibroblast growth factor gene and its preservation in leukemia patients . Oncogene . 6 . 9 . 1521–9 . September 1991 . 1717925 .
• Wu DQ, Kan MK, Sato GH, Okamoto T, Sato JD . Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors . The Journal of Biological Chemistry . 266 . 25 . 16778–85 . September 1991 . 10.1016/S0021-9258(18)55368-0 . 1885605 . free .
• Crumley G, Dionne CA, Jaye M . 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 . August 1990 . 2393407 . 10.1016/0006-291X(90)91348-V .
• Harper JW, Strydom DJ, Lobb RR . Human class 1 heparin-binding growth factor: structure and homology to bovine acidic brain fibroblast growth factor . Biochemistry . 25 . 14 . 4097–103 . July 1986 . 2427112 . 10.1021/bi00362a017 .
• Winkles JA, Friesel R, Burgess WH, Howk R, Mehlman T, Weinstein R, Maciag T . 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 . October 1987 . 2444975 . 299242 . 10.1073/pnas.84.20.7124 . 1987PNAS...84.7124W . free .
• Wang WP, Lehtoma K, Varban ML, Krishnan I, Chiu IM . 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 . June 1989 . 2474753 . 362312 . 10.1128/mcb.9.6.2387.
• Mergia A, Tischer E, Graves D, Tumolo A, Miller J, Gospodarowicz D, Abraham JA, Shipley GD, Fiddes JC . Structural analysis of the gene for human acidic fibroblast growth factor . Biochemical and Biophysical Research Communications . 164 . 3 . 1121–9 . November 1989 . 2590193 . 10.1016/0006-291X(89)91785-3 .
• Gimenez-Gallego G, Conn G, Hatcher VB, Thomas KA . The complete amino acid sequence of human brain-derived acidic fibroblast growth factor . Biochemical and Biophysical Research Communications . 138 . 2 . 611–7 . July 1986 . 3527167 . 10.1016/S0006-291X(86)80540-X .
• Gautschi P, Fràter-Schröder M, Böhlen P . Partial molecular characterization of endothelial cell mitogens from human brain: acidic and basic fibroblast growth factors . FEBS Letters . 204 . 2 . 203–7 . August 1986 . 3732516 . 10.1016/0014-5793(86)80812-2 . 22617694 . free . 1986FEBSL.204..203G .
• Gautschi-Sova P, Müller T, Böhlen P . Amino acid sequence of human acidic fibroblast growth factor . Biochemical and Biophysical Research Communications . 140 . 3 . 874–80 . November 1986 . 3778488 . 10.1016/0006-291X(86)90716-3 .
• Gimenez-Gallego G, Conn G, Hatcher VB, Thomas KA . 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 . March 1986 . 3964259 . 10.1016/0006-291X(86)90028-8 .
• Zhao XM, Yeoh TK, Hiebert M, Frist WH, Miller GG . 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 . November 1993 . 7504343 . 10.1097/00007890-199311000-00025 . free .
• Pineda-Lucena A, Jiménez MA, Nieto JL, Santoro J, Rico M, Giménez-Gallego G . 1H-NMR assignment and solution structure of human acidic fibroblast growth factor activated by inositol hexasulfate . Journal of Molecular Biology . 242 . 1 . 81–98 . September 1994 . 7521397 . 10.1006/jmbi.1994.1558 .
• Chotani MA, Payson RA, Winkles JA, Chiu IM . 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 . February 1995 . 7533902 . 306694 . 10.1093/nar/23.3.434 .
• Opalenik SR, Shin JT, Wehby JN, Mahesh VK, Thompson JA . 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 . July 1995 . 7542239 . 10.1074/jbc.270.29.17457 . free .
• Myers RL, Payson RA, Chotani MA, Deaven LL, Chiu IM . Gene structure and differential expression of acidic fibroblast growth factor mRNA: identification and distribution of four different transcripts . Oncogene . 8 . 2 . 341–9 . February 1993 . 7678925 .

Notes and References

1. Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J . 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 . September 1990 . 1697263 . 551973 . 10.1002/j.1460-2075.1990.tb07454.x.
2. Jaye M, Howk R, Burgess W, Ricca GA, Chiu IM, Ravera MW, O'Brien SJ, Modi WS, Maciag T, Drohan WN . Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization . Science . 233 . 4763 . 541–5 . August 1986 . 3523756 . 10.1126/science.3523756 . 1986Sci...233..541J .
3. Burgess WH, Maciag T . The heparin-binding (fibroblast) growth factor family of proteins . Annual Review of Biochemistry . 58 . 575–606 . 1989 . 2549857 . 10.1146/annurev.bi.58.070189.003043 .
4. Tarantini F, Gamble S, Jackson A, Maciag T . 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 . December 1995 . 7493920 . 10.1074/jbc.270.49.29039 . free .
5. Prudovsky I, Bagala C, Tarantini F, Mandinova A, Soldi R, Bellum S, Maciag T . 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 . July 2002 . 12135982 . 2173119 . 10.1083/jcb.200203084 .
6. Coleman SJ, Bruce C, Chioni AM, Kocher HM, Grose RP . The ins and outs of fibroblast growth factor receptor signalling . Clinical Science . 127 . 4 . 217–31 . August 2014 . 24780002 . 10.1042/CS20140100 .
7. Web site: Entrez Gene: FGF1 fibroblast growth factor 1 (acidic).
8. 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 . Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer . Nature . 513 . 7518 . 436–9 . September 2014 . 25043058 . 4184286 . 10.1038/nature13540 . 2014Natur.513..436S .
9. Skjerpen CS, Nilsen T, Wesche J, Olsnes S . Binding of FGF-1 variants to protein kinase CK2 correlates with mitogenicity . The EMBO Journal . 21 . 15 . 4058–69 . August 2002 . 12145206 . 126148 . 10.1093/emboj/cdf402 .
10. Kolpakova E, Wiedłocha A, Stenmark H, Klingenberg O, Falnes PO, Olsnes S . Cloning of an intracellular protein that binds selectively to mitogenic acidic fibroblast growth factor . The Biochemical Journal . 336 . 1 . 213–22 . November 1998 . 9806903 . 1219860 . 10.1042/bj3360213 .
11. Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M . 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 . September 2000 . 11030354 . 10.1016/s1097-2765(00)00073-3 . free .
12. Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM . Expression and biological activity of mouse fibroblast growth factor-9 . The Journal of Biological Chemistry . 271 . 3 . 1726–31 . January 1996 . 8576175 . 10.1074/jbc.271.3.1726 . free .
13. Stauber DJ, DiGabriele AD, Hendrickson WA . 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 . January 2000 . 10618369 . 26614 . 10.1073/pnas.97.1.49 . 2000PNAS...97...49S . free .
14. Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL . Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin . Nature . 407 . 6807 . 1029–34 . October 2000 . 11069186 . 10.1038/35039551 . 2000Natur.407.1029P . 4418272 .
15. Chellaiah A, Yuan W, Chellaiah M, Ornitz DM . 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 . December 1999 . 10574949 . 10.1074/jbc.274.49.34785 . free .
16. Loo BB, Darwish KK, Vainikka SS, Saarikettu JJ, Vihko PP, Hermonen JJ, Goldman AA, Alitalo KK, Jalkanen MM . 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 . May 2000 . 10736564 . 10.1016/S1357-2725(99)00145-4 .
17. Kan M, Wu X, Wang F, McKeehan WL . 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 . May 1999 . 10336501 . 10.1074/jbc.274.22.15947 . free .
18. Mizukoshi E, Suzuki M, Loupatov A, Uruno T, Hayashi H, Misono T, Kaul SC, Wadhwa R, Imamura T . Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin . The Biochemical Journal . 343 . 2 . 461–6 . October 1999 . 10510314 . 1220575 . 10.1042/0264-6021:3430461 .
19. Mouta Carreira C, LaVallee TM, Tarantini F, Jackson A, Lathrop JT, Hampton B, Burgess WH, Maciag T . 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 . August 1998 . 9712836 . 10.1074/jbc.273.35.22224 . free . 2158/26736 . free .
20. Landriscina M, Bagalá C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T . 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 . July 2001 . 11432880 . 10.1074/jbc.M102925200 . free.