Fibroblast growth factor 2 explained

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 FGF2 gene.^{[1] [2]} 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.^[3]

Function

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.

In normal tissue, bFGF is present in basement membranes and in the subendothelial extracellular matrix of blood vessels. It stays membrane-bound as long as there is no signal peptide.

It has been hypothesized that, during both wound healing of normal tissues and tumor development, the action of heparan sulfate-degrading enzymes activates bFGF, thus mediating the formation of new blood vessels, a process known as angiogenesis.

In addition, it is synthesized and secreted by human adipocytes and the concentration of FGF2 correlates with the BMI in blood samples. It was also shown to act on preosteoblasts – in the form of an increased proliferation – after binding to fibroblast growth factor receptor 1 and activating phosphoinositide 3-kinase.^[4]

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.^[5]

Evidence has shown that low levels of FGF-2 play a key role in the incidence of excessive anxiety.^[6]

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.^[7] It is necessary in mouse-feeder cell dependent culture systems, as well as in feeder and serum-free culture systems.^[8] 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.^[9] However, a low concentration of bFGF (10 ng/mL) may exert an inhibitory effect on osteoblast differentiation.^[10] The nuclear form of FGF2 functions in mRNA export

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.^[11] 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.^[12]

Since its first isolation from the bovine pituitary,^[13] 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.^[14] 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.^[15] 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.^[16] 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.^[17] Together, this showcases the key roles FGF2 plays in bovine embryo development, as similarly described in other mammalian species.

Interactions

Fibroblast growth factor 2 has been shown to interact with casein kinase 2, alpha 1,^[18] RPL6,^[19] ribosomal protein S19^[20] and API5.^[21]

See also

• Angiogenesis
• Anxiety disorders
• Cytokine
• Fibroblast growth factor
• Growth factor
• Proteases in angiogenesis
• Receptor (biochemistry)
• Signal transduction

Further reading

• Ornitz DM, Itoh N . Fibroblast growth factors . Genome Biology . 2 . 3 . REVIEWS3005 . 2001 . 11276432 . 138918 . 10.1186/gb-2001-2-3-reviews3005 . free .
• Orpana A, Salven P . Angiogenic and lymphangiogenic molecules in hematological malignancies . Leukemia & Lymphoma . 43 . 2 . 219–24 . February 2002 . 11999550 . 10.1080/10428190290005964 . 21908151 .
• Marie PJ, Debiais F, Haÿ E . Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling . Histology and Histopathology . 17 . 3 . 877–85 . 2003 . 12168799 . 10.14670/HH-17.877 .
• Zhao XC, Zhang LM, Tong DY, An P, Jiang C, Zhao P, Chen WM, Wang J . Propofol increases expression of basic fibroblast growth factor after transient cerebral ischemia in rats . Neurochemical Research . 38 . 3 . 530–7 . March 2013 . 23247820 . 3574197 . 10.1007/s11064-012-0945-4 .
• Vincent T, Saklatvala J . Basic fibroblast growth factor: an extracellular mechanotransducer in articular cartilage? . Biochemical Society Transactions . 34 . Pt 3 . 456–7 . June 2006 . 16709186 . 10.1042/BST0340456 .
• Ribatti D, Vacca A, Rusnati M, Presta M . 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 . 2007 . 17537668 . 10.1016/j.cytogfr.2007.04.011 .
• Watson R, Anthony F, Pickett M, Lambden P, Masson GM, Thomas EJ . 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 . September 1992 . 1417798 . 10.1016/0006-291X(92)90434-M .
• 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 .
• Eriksson AE, Cousens LS, Weaver LH, Matthews BW . Three-dimensional structure of human basic fibroblast growth factor . Proceedings of the National Academy of Sciences of the United States of America . 88 . 8 . 3441–5 . April 1991 . 1707542 . 51463 . 10.1073/pnas.88.8.3441 . 1991PNAS...88.3441E . free .
• Ago H, Kitagawa Y, Fujishima A, Matsuura Y, Katsube Y . Crystal structure of basic fibroblast growth factor at 1.6 A resolution . Journal of Biochemistry . 110 . 3 . 360–3 . September 1991 . 1769963 . 10.1093/oxfordjournals.jbchem.a123586. free .
• Zhang JD, Cousens LS, Barr PJ, Sprang SR . Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1 beta . Proceedings of the National Academy of Sciences of the United States of America . 88 . 8 . 3446–50 . April 1991 . 1849658 . 51464 . 10.1073/pnas.88.8.3446 . 1991PNAS...88.3446Z . free .
• 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 .
• Fukushima Y, Byers MG, Fiddes JC, Shows TB . The human basic fibroblast growth factor gene (FGFB) is assigned to chromosome 4q25 . Cytogenetics and Cell Genetics . 54 . 3–4 . 159–60 . 1991 . 2265560 . 10.1159/000132983 .
• Lafage-Pochitaloff M, Galland F, Simonetti J, Prats H, Mattei MG, Birnbaum D . 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 . 1990 . 2320377 .
• Story MT, Esch F, Shimasaki S, Sasse J, Jacobs SC, Lawson RK . 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 . February 1987 . 2435284 . 10.1016/0006-291X(87)91471-9 .
• Kurokawa T, Sasada R, Iwane M, Igarashi K . Cloning and expression of cDNA encoding human basic fibroblast growth factor . FEBS Letters . 213 . 1 . 189–94 . March 1987 . 2435575 . 10.1016/0014-5793(87)81489-8 . 28111330 . free .
• Prats H, Kaghad M, Prats AC, Klagsbrun M, Lélias JM, Liauzun P, Chalon P, Tauber JP, Amalric F, Smith JA . High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons . Proceedings of the National Academy of Sciences of the United States of America . 86 . 6 . 1836–40 . March 1989 . 2538817 . 286799 . 10.1073/pnas.86.6.1836 . 1989PNAS...86.1836P . free .
• Florkiewicz RZ, Sommer A . Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons . Proceedings of the National Academy of Sciences of the United States of America . 86 . 11 . 3978–81 . June 1989 . 2726761 . 287371 . 10.1073/pnas.86.11.3978 . 1989PNAS...86.3978F . free .
• Abraham JA, Whang JL, Tumolo A, Mergia A, Fiddes JC . 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 . 1987 . 3472745 . 10.1101/sqb.1986.051.01.078 .
• Sommer A, Brewer MT, Thompson RC, Moscatelli D, Presta M, Rifkin DB . A form of human basic fibroblast growth factor with an extended amino terminus . Biochemical and Biophysical Research Communications . 144 . 2 . 543–50 . April 1987 . 3579930 . 10.1016/S0006-291X(87)80001-3 .

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. Kim HS . 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 . 1998 . 9925931 . 10.1159/000015129 . 33214466 .
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. Kühn MC, Willenberg HS, Schott M, Papewalis C, Stumpf U, Flohé S, Scherbaum WA, Schinner S . Adipocyte-secreted factors increase osteoblast proliferation and the OPG/RANKL ratio to influence osteoclast formation . Molecular and Cellular Endocrinology . 349 . 2 . 180–8 . February 2012 . 22040599 . 10.1016/j.mce.2011.10.018 . 2305986 .
5. House SL, Bolte C, Zhou M, Doetschman T, Klevitsky R, Newman G, Schultz Jel J . Cardiac-specific overexpression of fibroblast growth factor-2 protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia . Circulation . 108 . 25 . 3140–8 . December 2003 . 14656920 . 10.1161/01.CIR.0000105723.91637.1C . 14251918 .
6. Perez JA, Clinton SM, Turner CA, Watson SJ, Akil H . A new role for FGF2 as an endogenous inhibitor of anxiety . The Journal of Neuroscience . 29 . 19 . 6379–87 . May 2009 . 19439615 . 2748795 . 10.1523/JNEUROSCI.4829-08.2009 .
7. Pereira RC, Economides AN, Canalis E . Bone morphogenetic proteins induce gremlin, a protein that limits their activity in osteoblasts . Endocrinology . 141 . 12 . 4558–63 . December 2000 . 11108268 . 10.1210/endo.141.12.7851 . free .
8. Liu Y, Song Z, Zhao Y, Qin H, Cai J, Zhang H, Yu T, Jiang S, Wang G, Ding M, Deng H . 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 . July 2006 . 16753134 . 10.1016/j.bbrc.2006.05.086 .
9. Lee TJ, Jang J, Kang S, Jin M, Shin H, Kim DW, Kim BS . 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 . January 2013 . 23206696 . 10.1016/j.bbrc.2012.11.067 .
10. Del Angel-Mosqueda C, Gutiérrez-Puente Y, López-Lozano AP, Romero-Zavaleta RE, Mendiola-Jiménez A, Medina-De la Garza CE, Márquez-M M, De la Garza-Ramos MA . Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro . Head & Face Medicine . 11 . 29 . September 2015 . 26334535 . 10.1186/s13005-015-0086-5 . 4558932 . free .
11. Florkiewicz RZ, Shibata F, Barankiewicz T, Baird A, Gonzalez AM, Florkiewicz E, Shah N . Basic fibroblast growth factor gene expression . Annals of the New York Academy of Sciences . 638 . 1 . 109–26 . December 1991 . 1785797 . 10.1111/j.1749-6632.1991.tb49022.x . 1991NYASA.638..109F . 45425517 .
12. 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 .
13. Benington L, Rajan G, Locher C, Lim LY . Fibroblast Growth Factor 2-A Review of Stabilisation Approaches for Clinical Applications . Pharmaceutics . 12 . 6 . 508 . June 2020 . 32498439 . 7356611 . 10.3390/pharmaceutics12060508 . free .
14. Barros RG, Lima PF, Soares AC, Sanches L, Price CA, Buratini J . Fibroblast growth factor 2 regulates cumulus differentiation under the control of the oocyte . Journal of Assisted Reproduction and Genetics . 36 . 5 . 905–913 . May 2019 . 30887159 . 6541720 . 10.1007/s10815-019-01436-7 .
15. Yang QE, Fields SD, Zhang K, Ozawa M, Johnson SE, Ealy AD . Fibroblast growth factor 2 promotes primitive endoderm development in bovine blastocyst outgrowths . Biology of Reproduction . 85 . 5 . 946–953 . November 2011 . 21778141 . 10.1095/biolreprod.111.093203 .
16. Fields SD, Hansen PJ, Ealy AD . Fibroblast growth factor requirements for in vitro development of bovine embryos . Theriogenology . 75 . 8 . 1466–1475 . May 2011 . 21295834 . 10.1016/j.theriogenology.2010.12.007 .
17. Xie M, McCoski SR, Johnson SE, Rhoads ML, Ealy AD . 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 . February 2017 . 26304178 . 10.1071/RD15226 .
18. 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 .
19. Shen B, Arese M, Gualandris A, Rifkin DB . Intracellular association of FGF-2 with the ribosomal protein L6/TAXREB107 . Biochemical and Biophysical Research Communications . 252 . 2 . 524–8 . November 1998 . 9826564 . 10.1006/bbrc.1998.9677 . free .
20. Soulet F, Al Saati T, Roga S, Amalric F, Bouche G . Fibroblast growth factor-2 interacts with free ribosomal protein S19 . Biochemical and Biophysical Research Communications . 289 . 2 . 591–6 . November 2001 . 11716516 . 10.1006/bbrc.2001.5960 .
21. Bong SM, Bae SH, Song B, Gwak H, Yang SW, Kim S, Nam S, Rajalingam K, Oh SJ, Kim TW, Park S, Jang H, Lee BI . Regulation of mRNA Export Through API5 and Nuclear FGF2 Interaction . Nucleic Acids Research . 48. 11. 6340–6352. June 2020 . 32383752 . 10.1093/nar/gkaa335 . 7293033 .