Fibroblast growth factor 2 (FGF-2), also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the FGF2gene.[5][6] It binds to and exerts effects via specific fibroblast growth factor receptor(FGFR) proteins, themselves a family of closely related molecules. Fibroblast growth factor protein was first purified in 1975; soon thereafter three variants were isolated: 'basic FGF' (FGF2); Heparin-binding growth factor-2; and Endothelial cell growth factor-2. Gene sequencing revealed that this group is the same FGF2 protein and is a member of a family of FGF proteins.[7][8]
Like other FGF family members, basic fibroblast growth factor possesses broad mitogenic and cell survival activities, and is involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.
FGF2 has been shown in preliminary animal studies to protect the heart from injury associated with a heart attack, reducing tissue death and promoting improved function after reperfusion.[10]
Evidence has shown that low levels of FGF-2 play a key role in the incidence of excessive anxiety.[11]
Additionally, FGF-2 is a critical component of human embryonic stem cell culture medium; the growth factor is necessary for the cells to remain in an undifferentiated state, although the mechanisms by which it does this are poorly defined. It has been demonstrated to induce gremlin expression which in turn is known to inhibit the induction of differentiation by bone morphogenetic proteins.[12] It is necessary in mouse-feeder cell dependent culture systems, as well as in feeder and serum-free culture systems.[13] FGF-2, in conjunction with BMP4, promote differentiation of stem cells to mesodermal lineages. After differentiation, BMP4 and FGF2 treated cells generally produce higher amounts of osteogenic and chondrogenic differentiation than untreated stem cells.[14] However, a low concentration of bFGF (10 ng/mL) may exert an inhibitory effect on osteoblastdifferentiation.[15] The nuclear form of FGF2 functions in mRNA export[16]
FGF-2 is synthesized primarily as a 155 amino acid polypeptide, resulting in an 18 kDa protein. However, there are four alternate start codons which provide N-terminal extensions of 41, 46, 55, or 133 amino acids, resulting in proteins of 22 kDa (196 aa total), 22.5 kDa (201 aa total), 24 kDa (210 aa total) and 34 kDa (288 aa total), respectively.[7] Generally, the 155 aa/18 kDa low molecular weight (LMW) form is considered cytoplasmic and can be secreted from the cell, whereas the high molecular weight (HMW) forms are directed to the cell's nucleus.[17]
Since its first isolation from the bovine pituitary,[18] FGF2 has become a prominent signaling protein studied in bovine reproduction. It has been found in cumulus cells that surround the oocyte and evidence on such early reproductive function indicates FGF2 may promote meiotic resumption and prevent cumulus cell apoptosis.[19] FGF2 is also produced by the uterine epithelium, secreted into the lumen, and acts on the developing embryo and conceptus. Work in mice previously established that FGF2 plays a role in primitive endoderm (PE) development.[20] Research with bovine embryos has since noted this same phenomenon. Extended blastocyst cultures with FGF2-supplemented media observed that FGF2 increases PE outgrowths via proliferation. Knockout models of the FGF receptor and its kinase activity appears to alter the cellular expression of NANOG and GATA4 (transcription factors essential for proper cell differentiation and embryonic development), indicating a specific role of FGF2 in PE specification and subsequent blastocyst development rates.[20][21] Culture media supplemented with combinations of FGF2, EGF and IGF2 have found similar results and indicate that FGF2 may activate the AKT pathway for trophoblastic cell line growth.[22] Together, this showcases the key roles FGF2 plays in bovine embryo development, as similarly described in other mammalian species.
^Kim HS (1998). "Assignment1 of the human basic fibroblast growth factor gene FGF2 to chromosome 4 band q26 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 83 (1–2): 73. doi:10.1159/000015129. PMID9925931. S2CID33214466.
^Liu Y, Song Z, Zhao Y, Qin H, Cai J, Zhang H, Yu T, Jiang S, Wang G, Ding M, Deng H (July 2006). "A novel chemical-defined medium with bFGF and N2B27 supplements supports undifferentiated growth in human embryonic stem cells". Biochemical and Biophysical Research Communications. 346 (1): 131–9. doi:10.1016/j.bbrc.2006.05.086. PMID16753134.
^Lee TJ, Jang J, Kang S, Jin M, Shin H, Kim DW, Kim BS (January 2013). "Enhancement of osteogenic and chondrogenic differentiation of human embryonic stem cells by mesodermal lineage induction with BMP-4 and FGF2 treatment". Biochemical and Biophysical Research Communications. 430 (2): 793–7. doi:10.1016/j.bbrc.2012.11.067. PMID23206696.
^ abYang QE, Fields SD, Zhang K, Ozawa M, Johnson SE, Ealy AD (November 2011). "Fibroblast growth factor 2 promotes primitive endoderm development in bovine blastocyst outgrowths". Biology of Reproduction. 85 (5): 946–953. doi:10.1095/biolreprod.111.093203. PMID21778141.
^Fields SD, Hansen PJ, Ealy AD (May 2011). "Fibroblast growth factor requirements for in vitro development of bovine embryos". Theriogenology. 75 (8): 1466–1475. doi:10.1016/j.theriogenology.2010.12.007. PMID21295834.
^Xie M, McCoski SR, Johnson SE, Rhoads ML, Ealy AD (February 2017). "Combinatorial effects of epidermal growth factor, fibroblast growth factor 2 and insulin-like growth factor 1 on trophoblast cell proliferation and embryogenesis in cattle". Reproduction, Fertility, and Development. 29 (2): 419–430. doi:10.1071/RD15226. PMID26304178.
Marie PJ, Debiais F, Haÿ E (2003). "Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling". Histology and Histopathology. 17 (3): 877–85. doi:10.14670/HH-17.877. PMID12168799.
Vincent T, Saklatvala J (June 2006). "Basic fibroblast growth factor: an extracellular mechanotransducer in articular cartilage?". Biochemical Society Transactions. 34 (Pt 3): 456–7. doi:10.1042/BST0340456. PMID16709186.
Ribatti D, Vacca A, Rusnati M, Presta M (2007). "The discovery of basic fibroblast growth factor/fibroblast growth factor-2 and its role in haematological malignancies". Cytokine & Growth Factor Reviews. 18 (3–4): 327–34. doi:10.1016/j.cytogfr.2007.04.011. PMID17537668.
Watson R, Anthony F, Pickett M, Lambden P, Masson GM, Thomas EJ (September 1992). "Reverse transcription with nested polymerase chain reaction shows expression of basic fibroblast growth factor transcripts in human granulosa and cumulus cells from in vitro fertilisation patients". Biochemical and Biophysical Research Communications. 187 (3): 1227–31. doi:10.1016/0006-291X(92)90434-M. PMID1417798.
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.
Fukushima Y, Byers MG, Fiddes JC, Shows TB (1991). "The human basic fibroblast growth factor gene (FGFB) is assigned to chromosome 4q25". Cytogenetics and Cell Genetics. 54 (3–4): 159–60. doi:10.1159/000132983. PMID2265560.
Lafage-Pochitaloff M, Galland F, Simonetti J, Prats H, Mattei MG, Birnbaum D (1990). "The human basic fibroblast growth factor gene is located on the long arm of chromosome 4 at bands q26-q27". Oncogene Research. 5 (3): 241–4. PMID2320377.
Story MT, Esch F, Shimasaki S, Sasse J, Jacobs SC, Lawson RK (February 1987). "Amino-terminal sequence of a large form of basic fibroblast growth factor isolated from human benign prostatic hyperplastic tissue". Biochemical and Biophysical Research Communications. 142 (3): 702–9. doi:10.1016/0006-291X(87)91471-9. PMID2435284.
Abraham JA, Whang JL, Tumolo A, Mergia A, Fiddes JC (1987). "Human basic fibroblast growth factor: nucleotide sequence, genomic organization, and expression in mammalian cells". Cold Spring Harbor Symposia on Quantitative Biology. 51 Pt 1: 657–68. doi:10.1101/sqb.1986.051.01.078. PMID3472745.
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1bas: THREE-DIMENSIONAL STRUCTURES OF ACIDIC AND BASIC FIBROBLAST GROWTH FACTORS
1bfb: BASIC FIBROBLAST GROWTH FACTOR COMPLEXED WITH HEPARIN TETRAMER FRAGMENT
1bfc: BASIC FIBROBLAST GROWTH FACTOR COMPLEXED WITH HEPARIN HEXAMER FRAGMENT
1bff: THE 154 AMINO ACID FORM OF HUMAN BASIC FIBROBLAST GROWTH FACTOR
1bfg: CRYSTAL STRUCTURE OF BASIC FIBROBLAST GROWTH FACTOR AT 1.6 ANGSTROMS RESOLUTION
1bla: BASIC FIBROBLAST GROWTH FACTOR (FGF-2) MUTANT WITH CYS 78 REPLACED BY SER AND CYS 96 REPLACED BY SER, NMR
1bld: BASIC FIBROBLAST GROWTH FACTOR (FGF-2) MUTANT WITH CYS 78 REPLACED BY SER AND CYS 96 REPLACED BY SER, NMR
1cvs: CRYSTAL STRUCTURE OF A DIMERIC FGF2-FGFR1 COMPLEX
1ev2: CRYSTAL STRUCTURE OF FGF2 IN COMPLEX WITH THE EXTRACELLULAR LIGAND BINDING DOMAIN OF FGF RECEPTOR 2 (FGFR2)
1fga: REFINEMENT OF THE STRUCTURE OF HUMAN BASIC FIBROBLAST GROWTH FACTOR AT 1.6 ANGSTROMS RESOLUTION AND ANALYSIS OF PRESUMED HEPARIN BINDING SITES BY SELENATE SUBSTITUTION
1fq9: CRYSTAL STRUCTURE OF A TERNARY FGF2-FGFR1-HEPARIN COMPLEX
1ii4: CRYSTAL STRUCTURE OF SER252TRP APERT MUTANT FGF RECEPTOR 2 (FGFR2) IN COMPLEX WITH FGF2
1iil: CRYSTAL STRUCTURE OF PRO253ARG APERT MUTANT FGF RECEPTOR 2 (FGFR2) IN COMPLEX WITH FGF2
2bfh: CRYSTAL STRUCTURE OF BASIC FIBROBLAST GROWTH FACTOR AT 1.6 ANGSTROMS RESOLUTION
2fgf: THREE-DIMENSIONAL STRUCTURE OF HUMAN BASIC FIBROBLAST GROWTH FACTOR, A STRUCTURAL HOMOLOG OF INTERLEUKIN 1BETA
4fgf: REFINEMENT OF THE STRUCTURE OF HUMAN BASIC FIBROBLAST GROWTH FACTOR AT 1.6 ANGSTROMS RESOLUTION AND ANALYSIS OF PRESUMED HEPARIN BINDING SITES BY SELENATE SUBSTITUTION
