Fibroblast growth factor 2

FGF2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1BAS, 1BFB, 1BFC, 1BFF, 1BFG, 1BLA, 1BLD, 1CVS, 1EV2, 1FGA, 1FQ9, 1II4, 1IIL, 2BFH, 2FGF, 2M49, 4FGF, 4OEE, 4OEF, 4OEG
Identifiers
Aliases	FGF2, BFGF, FGF-2, FGFB, HBGF-2, fibroblast growth factor 2
External IDs	OMIM: 134920; MGI: 95516; HomoloGene: 1521; GeneCards: FGF2; OMA:FGF2 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q28.1 Start 122,826,708 bp[1] End 122,898,236 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 B|3 18.41 cM Start 37,402,495 bp[2] End 37,464,257 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cartilage tissue Epithelium of choroid plexus Achilles tendon smooth muscle tissue stromal cell of endometrium Descending thoracic aorta adipose tissue retinal pigment epithelium subcutaneous adipose tissue muscle layer of sigmoid colon Top expressed in ascending aorta aortic valve vas deferens efferent ductule ankle decidua gastrula epididymis carotid body esophagus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity heparin binding fibroblast growth factor receptor binding protein binding nuclear receptor coactivator activity chemoattractant activity growth factor activity protein tyrosine kinase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity 1-phosphatidylinositol-3-kinase activity receptor-receptor interaction integrin binding Cellular component extracellular region nucleus extracellular space Biological process release of sequestered calcium ion into cytosol cell differentiation negative regulation of fibroblast migration hyaluronan catabolic process positive regulation of endothelial cell proliferation positive regulation of MAP kinase activity negative regulation of blood vessel endothelial cell migration positive regulation of endothelial cell chemotaxis to fibroblast growth factor somatic stem cell population maintenance positive regulation of phospholipase C activity extracellular matrix organization wound healing negative regulation of cell death regulation of angiogenesis nervous system development cell migration involved in sprouting angiogenesis MAPK cascade positive regulation of angiogenesis positive regulation of phosphatidylinositol 3-kinase activity positive regulation of transcription, DNA-templated chemotaxis fibroblast growth factor receptor signaling pathway chondroblast differentiation multicellular organism development growth factor dependent regulation of skeletal muscle satellite cell proliferation branching involved in ureteric bud morphogenesis positive regulation of cardiac muscle cell proliferation embryonic morphogenesis angiogenesis positive regulation of cell fate specification animal organ morphogenesis regulation of endothelial cell chemotaxis to fibroblast growth factor phosphatidylinositol biosynthetic process inositol phosphate biosynthetic process negative regulation of wound healing Ras protein signal transduction positive regulation of cell division signal transduction positive regulation of transcription by RNA polymerase II positive chemotaxis phosphatidylinositol phosphate biosynthetic process peptidyl-tyrosine phosphorylation positive regulation of sprouting angiogenesis positive regulation of cell population proliferation phosphatidylinositol-3-phosphate biosynthetic process stem cell proliferation regulation of signaling receptor activity positive regulation of protein kinase B signaling cytokine-mediated signaling pathway positive regulation of blood vessel endothelial cell migration positive regulation of ERK1 and ERK2 cascade positive regulation of vascular associated smooth muscle cell proliferation positive regulation of vascular endothelial cell proliferation positive regulation of cell migration involved in sprouting angiogenesis paracrine signaling positive regulation of DNA biosynthetic process positive regulation of endothelial cell chemotaxis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2247 14173 Ensembl ENSG00000138685 ENSMUSG00000037225 UniProt P09038 P15655 RefSeq (mRNA) NM_002006 NM_001361665 NM_008006 RefSeq (protein) NP_001997 NP_001348594 NP_032032 Location (UCSC) Chr 4: 122.83 – 122.9 Mb Chr 3: 37.4 – 37.46 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.[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]

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.[9]

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 osteoblast differentiation.[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.

Interactions

Fibroblast growth factor 2 has been shown to interact with casein kinase 2, alpha 1,[23] RPL6,[24] ribosomal protein S19[25] and API5.[16]

See also

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

References

1. GRCh38: Ensembl release 89: ENSG00000138685 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037225 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J (September 1990). "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. doi:10.1002/j.1460-2075.1990.tb07454.x. PMC 551973. PMID 1697263.
6. 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. PMID 9925931. S2CID 33214466.
7. Florkiewicz RZ, Shibata F, Barankiewicz T, Baird A, Gonzalez AM, Florkiewicz E, Shah N (December 1991). "Basic fibroblast growth factor gene expression". Annals of the New York Academy of Sciences. 638 (1): 109–26. Bibcode:1991NYASA.638..109F. doi:10.1111/j.1749-6632.1991.tb49022.x. PMID 1785797. S2CID 45425517.
8. Burgess WH, Maciag T (1989). "The heparin-binding (fibroblast) growth factor family of proteins". Annual Review of Biochemistry. 58: 575–606. doi:10.1146/annurev.bi.58.070189.003043. PMID 2549857.
9. Kühn MC, Willenberg HS, Schott M, Papewalis C, Stumpf U, Flohé S, Scherbaum WA, Schinner S (February 2012). "Adipocyte-secreted factors increase osteoblast proliferation and the OPG/RANKL ratio to influence osteoclast formation". Molecular and Cellular Endocrinology. 349 (2): 180–8. doi:10.1016/j.mce.2011.10.018. PMID 22040599. S2CID 2305986.
10. House SL, Bolte C, Zhou M, Doetschman T, Klevitsky R, Newman G, Schultz Jel J (December 2003). "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. doi:10.1161/01.CIR.0000105723.91637.1C. PMID 14656920. S2CID 14251918.
11. Perez JA, Clinton SM, Turner CA, Watson SJ, Akil H (May 2009). "A new role for FGF2 as an endogenous inhibitor of anxiety". The Journal of Neuroscience. 29 (19): 6379–87. doi:10.1523/JNEUROSCI.4829-08.2009. PMC 2748795. PMID 19439615.
12. Pereira RC, Economides AN, Canalis E (December 2000). "Bone morphogenetic proteins induce gremlin, a protein that limits their activity in osteoblasts". Endocrinology. 141 (12): 4558–63. doi:10.1210/endo.141.12.7851. PMID 11108268.
13. 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. PMID 16753134.
14. 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. PMID 23206696.
15. 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 (September 2015). "Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro". Head & Face Medicine. 11: 29. doi:10.1186/s13005-015-0086-5. PMC 4558932. PMID 26334535.
16. 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 (June 2020). "Regulation of mRNA Export Through API5 and Nuclear FGF2 Interaction". Nucleic Acids Research. 48 (11): 6340–6352. doi:10.1093/nar/gkaa335. PMC 7293033. PMID 32383752.
17. Coleman 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. PMID 24780002.
18. Benington L, Rajan G, Locher C, Lim LY (June 2020). "Fibroblast Growth Factor 2-A Review of Stabilisation Approaches for Clinical Applications". Pharmaceutics. 12 (6): 508. doi:10.3390/pharmaceutics12060508. PMC 7356611. PMID 32498439.
19. Barros RG, Lima PF, Soares AC, Sanches L, Price CA, Buratini J (May 2019). "Fibroblast growth factor 2 regulates cumulus differentiation under the control of the oocyte". Journal of Assisted Reproduction and Genetics. 36 (5): 905–913. doi:10.1007/s10815-019-01436-7. PMC 6541720. PMID 30887159.
20. Yang 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. PMID 21778141.
21. 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. PMID 21295834.
22. 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. PMID 26304178.
23. Skjerpen CS, Nilsen T, Wesche J, Olsnes S (August 2002). "Binding of FGF-1 variants to protein kinase CK2 correlates with mitogenicity". The EMBO Journal. 21 (15): 4058–69. doi:10.1093/emboj/cdf402. PMC 126148. PMID 12145206.
24. Shen B, Arese M, Gualandris A, Rifkin DB (November 1998). "Intracellular association of FGF-2 with the ribosomal protein L6/TAXREB107". Biochemical and Biophysical Research Communications. 252 (2): 524–8. doi:10.1006/bbrc.1998.9677. PMID 9826564.
25. Soulet F, Al Saati T, Roga S, Amalric F, Bouche G (November 2001). "Fibroblast growth factor-2 interacts with free ribosomal protein S19". Biochemical and Biophysical Research Communications. 289 (2): 591–6. doi:10.1006/bbrc.2001.5960. PMID 11716516.

Further reading

• Ornitz DM, Itoh N (2001). "Fibroblast growth factors". Genome Biology. 2 (3): REVIEWS3005. doi:10.1186/gb-2001-2-3-reviews3005. PMC 138918. PMID 11276432.
• Orpana A, Salven P (February 2002). "Angiogenic and lymphangiogenic molecules in hematological malignancies". Leukemia & Lymphoma. 43 (2): 219–24. doi:10.1080/10428190290005964. PMID 11999550. S2CID 21908151.
• 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. PMID 12168799.
• Zhao XC, Zhang LM, Tong DY, An P, Jiang C, Zhao P, Chen WM, Wang J (March 2013). "Propofol increases expression of basic fibroblast growth factor after transient cerebral ischemia in rats". Neurochemical Research. 38 (3): 530–7. doi:10.1007/s11064-012-0945-4. PMC 3574197. PMID 23247820.
• 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. PMID 16709186.
• 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. PMID 17537668.
• 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. PMID 1417798.
• 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. PMID 1702556.
• Eriksson AE, Cousens LS, Weaver LH, Matthews BW (April 1991). "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. Bibcode:1991PNAS...88.3441E. doi:10.1073/pnas.88.8.3441. PMC 51463. PMID 1707542.
• Ago H, Kitagawa Y, Fujishima A, Matsuura Y, Katsube Y (September 1991). "Crystal structure of basic fibroblast growth factor at 1.6 A resolution". Journal of Biochemistry. 110 (3): 360–3. doi:10.1093/oxfordjournals.jbchem.a123586. PMID 1769963.
• Zhang JD, Cousens LS, Barr PJ, Sprang SR (April 1991). "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. Bibcode:1991PNAS...88.3446Z. doi:10.1073/pnas.88.8.3446. PMC 51464. PMID 1849658.
• 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. doi:10.1016/S0021-9258(18)55368-0. PMID 1885605.
• 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. PMID 2265560.
• 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. PMID 2320377.
• 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. PMID 2435284.
• Kurokawa T, Sasada R, Iwane M, Igarashi K (March 1987). "Cloning and expression of cDNA encoding human basic fibroblast growth factor". FEBS Letters. 213 (1): 189–94. doi:10.1016/0014-5793(87)81489-8. PMID 2435575. S2CID 28111330.
• Prats H, Kaghad M, Prats AC, Klagsbrun M, Lélias JM, Liauzun P, Chalon P, Tauber JP, Amalric F, Smith JA (March 1989). "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. Bibcode:1989PNAS...86.1836P. doi:10.1073/pnas.86.6.1836. PMC 286799. PMID 2538817.
• Florkiewicz RZ, Sommer A (June 1989). "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. Bibcode:1989PNAS...86.3978F. doi:10.1073/pnas.86.11.3978. PMC 287371. PMID 2726761.
• 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. PMID 3472745.
• Sommer A, Brewer MT, Thompson RC, Moscatelli D, Presta M, Rifkin DB (April 1987). "A form of human basic fibroblast growth factor with an extended amino terminus". Biochemical and Biophysical Research Communications. 144 (2): 543–50. doi:10.1016/S0006-291X(87)80001-3. PMID 3579930.

External links

• Basic+Fibroblast+Growth+Factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human FGF2 genome location and FGF2 gene details page in the UCSC Genome Browser.