FGF1, also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1gene.[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.[6] 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.
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]
↑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. doi:10.1016/s1097-2765(00)00073-3. PMID11030354.
↑ 12.012.112.2Santos-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. doi:10.1074/jbc.271.3.1726. PMID8576175.
↑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. doi:10.1038/35039551. PMID11069186.
↑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. doi:10.1074/jbc.274.49.34785. PMID10574949.
↑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. doi:10.1016/S1357-2725(99)00145-4. PMID10736564.
↑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. doi:10.1074/jbc.274.22.15947. PMID10336501.
↑ 19.019.1Mouta 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. doi:10.1074/jbc.273.35.22224. PMID9712836.
↑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. doi:10.1074/jbc.M102925200. PMID11432880.
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. PMID1693186.
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. doi:10.1126/science.1702556. PMID1702556.
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. PMID1717925.
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. PMID1885605.
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. doi:10.1016/0006-291X(90)91348-V. PMID2393407.
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. doi:10.1021/bi00362a017. PMID2427112.
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. doi:10.1016/0006-291X(89)91785-3. PMID2590193.
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. doi:10.1016/S0006-291X(86)80540-X. PMID3527167.
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. doi:10.1016/0014-5793(86)80812-2. PMID3732516.
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. doi:10.1016/0006-291X(86)90716-3. PMID3778488.
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. doi:10.1016/0006-291X(86)90028-8. PMID3964259.
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. doi:10.1097/00007890-199311000-00025. PMID7504343.
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. doi:10.1006/jmbi.1994.1558. PMID7521397.
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. doi:10.1074/jbc.270.29.17457. PMID7542239.
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. PMID7678925.
1afc: STRUCTURAL STUDIES OF THE BINDING OF THE ANTI-ULCER DRUG SUCROSE OCTASULFATE TO ACIDIC FIBROBLAST GROWTH FACTOR
PDB 1axm EBI.jpg
1axm: HEPARIN-LINKED BIOLOGICALLY-ACTIVE DIMER OF FIBROBLAST GROWTH FACTOR
PDB 1bar EBI.jpg
1bar: THREE-DIMENSIONAL STRUCTURES OF ACIDIC AND BASIC FIBROBLAST GROWTH FACTORS
PDB 1djs EBI.jpg
1djs: LIGAND-BINDING PORTION OF FIBROBLAST GROWTH FACTOR RECEPTOR 2 IN COMPLEX WITH FGF1
PDB 1dzc EBI.jpg
1dzc: HIGH RESOLUTION STRUCTURE OF ACIDIC FIBROBLAST GROWTH FACTOR. MUTANT FGF-4-ALA-(23-154), 24 NMR STRUCTURES
PDB 1dzd EBI.jpg
1dzd: HIGH RESOLUTION STRUCTURE OF ACIDIC FIBROBLAST GROWTH FACTOR (27-154), 24 NMR STRUCTURES
PDB 1e0o EBI.jpg
1e0o: CRYSTAL STRUCTURE OF A TERNARY FGF1-FGFR2-HEPARIN COMPLEX
PDB 1evt EBI.jpg
1evt: CRYSTAL STRUCTURE OF FGF1 IN COMPLEX WITH THE EXTRACELLULAR LIGAND BINDING DOMAIN OF FGF RECEPTOR 1 (FGFR1)
PDB 1hkn EBI.jpg
1hkn: A COMPLEX BETWEEN ACIDIC FIBROBLAST GROWTH FACTOR AND 5-AMINO-2-NAPHTHALENESULFONATE
PDB 1jqz EBI.jpg
1jqz: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag.
PDB 1jt3 EBI.jpg
1jt3: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Histidine Tag AND LEU 73 REPLACED BY VAL (L73V)
PDB 1jt4 EBI.jpg
1jt4: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag AND VAL 109 REPLACED BY LEU (V109L)
PDB 1jt5 EBI.jpg
1jt5: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag AND LEU 73 REPLACED BY VAL AND VAL 109 REPLACED BY LEU (L73V/V109L)
PDB 1jt7 EBI.jpg
1jt7: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag AND LEU 44 REPLACED BY PHE AND LEU 73 REPLACED BY VAL AND VAL 109 REPLACED BY LEU (L44F/L73V/V109L)
PDB 1jtc EBI.jpg
1jtc: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag AND LEU 44 REPLACED BY PHE (L44F)
PDB 1jy0 EBI.jpg
1jy0: Human acidic fibroblast growth factor. 141 amino acid form with amino terminal His tag and Cys 117 replaced with Val (C117V).
PDB 1k5u EBI.jpg
1k5u: Human acidic fibroblast growth factor. 141 amino acid form with amino terminal His tag with His93 replaced by Gly (H93G).
PDB 1k5v EBI.jpg
1k5v: Human acidic fibroblast growth factor. 141 amino acid form with amino terminal His tag with Asn106 replaced by Gly (N106G).
PDB 1m16 EBI.jpg
1m16: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag and Leu 44 Replaced with Phe (L44F), Leu 73 Replaced with Val (L73V), Val 109 Replaced with Leu (V109L) and Cys 117 Replaced with Val (C117V).
PDB 1nzk EBI.jpg
1nzk: Crystal Structure of a Multiple Mutant (L44F, L73V, V109L, L111I, C117V) of Human Acidic Fibroblast Growth Factor
PDB 1p63 EBI.jpg
1p63: Human Acidic Fibroblast Growth Factor. 140 Amino Acid Form with Amino Terminal His Tag and Leu111 Replaced with Ile (L111I)
PDB 1pzz EBI.jpg
1pzz: Crystal structure of FGF-1, V51N mutant
PDB 1q03 EBI.jpg
1q03: Crystal structure of FGF-1, S50G/V51G mutant
PDB 1q04 EBI.jpg
1q04: Crystal structure of FGF-1, S50E/V51N
PDB 1rg8 EBI.jpg
1rg8: Human Acidic Fibroblast Growth Factor (haFGF-1) at 1.10 angstrom resolution (140 amino acid form)
PDB 1rml EBI.jpg
1rml: NMR STUDY OF ACID FIBROBLAST GROWTH FACTOR BOUND TO 1,3,6-NAPHTHALENE TRISULPHONATE, 26 STRUCTURES
PDB 1ry7 EBI.jpg
1ry7: Crystal Structure of the 3 Ig form of FGFR3c in complex with FGF1
PDB 1yto EBI.png
1yto: Crystal Structure of Gly19 deletion Mutant of Human Acidic Fibroblast Growth Factor
PDB 1z2v EBI.png
1z2v: Crystal Structure of Glu60 deletion Mutant of Human Acidic Fibroblast Growth Factor
PDB 1z4s EBI.png
1z4s: Crystal Structure of Gly19 and Glu60 deletion mutant of Human Acidic Fibroblast Growth Factor
PDB 2afg EBI.jpg
2afg: 2.0 ANGSTROM X-RAY STRUCTURE OF HUMAN ACIDIC FIBROBLAST GROWTH FACTOR
PDB 2aqz EBI.png
2aqz: Crystal structure of FGF-1, S17T/N18T/G19 deletion mutant
PDB 2axm EBI.jpg
2axm: HEPARIN-LINKED BIOLOGICALLY-ACTIVE DIMER OF FIBROBLAST GROWTH FACTOR
PDB 2erm EBI.jpg
2erm: Solution structure of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue