Fibroblast growth factor 1(FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1gene.[5][6] 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.[7] 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.[8][9] 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.[10]
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.[10] 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.[citation needed]
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.[11]
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.[12]
^ abColeman 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. doi:10.1042/CS20140100. PMID24780002.
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. Bibcode:1991Sci...251...90Z. 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.
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-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.
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.
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
1axm: HEPARIN-LINKED BIOLOGICALLY-ACTIVE DIMER OF FIBROBLAST GROWTH FACTOR
1bar: THREE-DIMENSIONAL STRUCTURES OF ACIDIC AND BASIC FIBROBLAST GROWTH FACTORS
1djs: LIGAND-BINDING PORTION OF FIBROBLAST GROWTH FACTOR RECEPTOR 2 IN COMPLEX WITH FGF1
1dzc: HIGH RESOLUTION STRUCTURE OF ACIDIC FIBROBLAST GROWTH FACTOR. MUTANT FGF-4-ALA-(23-154), 24 NMR STRUCTURES
1dzd: HIGH RESOLUTION STRUCTURE OF ACIDIC FIBROBLAST GROWTH FACTOR (27-154), 24 NMR STRUCTURES
1e0o: CRYSTAL STRUCTURE OF A TERNARY FGF1-FGFR2-HEPARIN COMPLEX
1evt: CRYSTAL STRUCTURE OF FGF1 IN COMPLEX WITH THE EXTRACELLULAR LIGAND BINDING DOMAIN OF FGF RECEPTOR 1 (FGFR1)
1hkn: A COMPLEX BETWEEN ACIDIC FIBROBLAST GROWTH FACTOR AND 5-AMINO-2-NAPHTHALENESULFONATE
1jqz: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag.
1jt3: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Histidine Tag AND LEU 73 REPLACED BY VAL (L73V)
1jt4: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag AND VAL 109 REPLACED BY LEU (V109L)
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)
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)
1jtc: Human Acidic Fibroblast Growth Factor. 141 Amino Acid Form with Amino Terminal His Tag AND LEU 44 REPLACED BY PHE (L44F)
1jy0: Human acidic fibroblast growth factor. 141 amino acid form with amino terminal His tag and Cys 117 replaced with Val (C117V).
1k5u: Human acidic fibroblast growth factor. 141 amino acid form with amino terminal His tag with His93 replaced by Gly (H93G).
1k5v: Human acidic fibroblast growth factor. 141 amino acid form with amino terminal His tag with Asn106 replaced by Gly (N106G).
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).
1nzk: Crystal Structure of a Multiple Mutant (L44F, L73V, V109L, L111I, C117V) of Human Acidic Fibroblast Growth Factor
1p63: Human Acidic Fibroblast Growth Factor. 140 Amino Acid Form with Amino Terminal His Tag and Leu111 Replaced with Ile (L111I)
1pzz: Crystal structure of FGF-1, V51N mutant
1q03: Crystal structure of FGF-1, S50G/V51G mutant
1q04: Crystal structure of FGF-1, S50E/V51N
1rg8: Human Acidic Fibroblast Growth Factor (haFGF-1) at 1.10 angstrom resolution (140 amino acid form)
1rml: NMR STUDY OF ACID FIBROBLAST GROWTH FACTOR BOUND TO 1,3,6-NAPHTHALENE TRISULPHONATE, 26 STRUCTURES
1ry7: Crystal Structure of the 3 Ig form of FGFR3c in complex with FGF1
1yto: Crystal Structure of Gly19 deletion Mutant of Human Acidic Fibroblast Growth Factor
1z2v: Crystal Structure of Glu60 deletion Mutant of Human Acidic Fibroblast Growth Factor
1z4s: Crystal Structure of Gly19 and Glu60 deletion mutant of Human Acidic Fibroblast Growth Factor
2afg: 2.0 ANGSTROM X-RAY STRUCTURE OF HUMAN ACIDIC FIBROBLAST GROWTH FACTOR
2aqz: Crystal structure of FGF-1, S17T/N18T/G19 deletion mutant
2axm: HEPARIN-LINKED BIOLOGICALLY-ACTIVE DIMER OF FIBROBLAST GROWTH FACTOR
2erm: Solution structure of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue
