Fibroblast growth factor

Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction. FGFs are key-players in the processes of proliferation and differentiation of cells, particularly endothelial cells; they ( especially FGF-1) promote angiogenesis^[1].

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Families

In humans, 23 members of the FGF family have been identified all of which are structurally related signaling molecules:^[2][3][4]

• Members FGF1 through FGF10 all bind fibroblast growth factor receptors (FGFRs). FGF1 is also known as "Acidic", and FGF2 is also known as basic fibroblast growth factor.
• Members FGF11, FGF12, FGF13, and FGF14, also known as FGF homologous factors 1-4 (FHF1-FHF4), have been shown to have distinct functional differences compared to the FGFs. Although these factors possess remarkably similar sequence homology, they do not bind FGFRs and are involved in intracellular processes unrelated to the FGFs.^[5]
• Members FGF16 through FGF23 are newer and not as well characterized. FGF-15 is the mouse ortholog of human FGF-19.

Receptors

The fibroblast growth factor receptor family consists of 4 members, FGFR1, FGFR2, FGFR3, and FGFR4.

Alternate mRNA splicing gives rise to multiple mRNA splice variants, of which the FGFR2IIIb splice variant encode isoform 2, the canonical FGF-10 receptor. 13 protein receptor isoforms are derived from the FGFR2 gene, e.ge., and the active sites differ significantly in their ligand-binding profiles.

The signaling complex at the cell surface is believed to be a ternary complex formed between two identical FGF ligands, two identical FGFR subunits and either one or two heparan (dermatan and/or chondroitin) sulfate chains.

History

Fibroblast growth factor was found in a cow brain extract by Gospodarowicz and colleagues and tested in a bioassay which caused fibroblasts to proliferate (first published report in 1974).^[6]

They then further fractionated the extract using acidic and basic pH and isolated two slightly different forms that were named "acidic fibroblast growth factor" (FGF-1) and "basic fibroblast growth factor" (FGF-2). These proteins had a high degree of amino acid identity but were determined to be distinct mitogens. Human FGF-2 occurs in low molecular weight (LMW) and high molecular weight (HMW) isoforms.^[7] LMW FGF-2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF-2s are nuclear and exert activities through an intracrine mechanism.

Not long after FGF-1 and FGF-2 were isolated, another group isolated a pair of heparin-binding growth factors which they named HBGF-1 and HBGF-2, whilst a third group isolated a pair of growth factors that caused proliferation of cells in a bioassay containing blood vessel endothelium cells which they called ECGF-1 and ECGF-2. These proteins were found to be identical to the acidic and basic FGFs described by Gospodarowicz and coworkers.

Function

One of the most important functions of aFGF (FGF-1) and bFGF (FGF-2) is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures. It thus promotes angiogenesis, the growth of new blood vessels from the pre-existing vasculature. aFGF is a more potent angiogenic factor than VEGF (vascular endothelial growth factor) or PDGF (platelet-derived growth factor). As well as stimulating blood vessel growth, aFGF and bFGF are important players in wound healing. They stimulate angiogenesis and the proliferation of fibroblasts that give rise to granulation tissue, which fills up a wound space/cavity early in the wound healing process.

It has also been demonstrated that fibroblast growth factors are associated with many developmental processes including mesoderm induction, antero-posterior patterning, neural induction, angiogenesis, axon extension and limb formation.^[8]

FGFs are crucial for the normal development of both vertebrates and invertebrates and any irregularities in their function leads to a range of developmental defects.^{[9] [10] [11] [12]}

See also

• granulocyte-colony stimulating factor (G-CSF)
• granulocyte-macrophage colony stimulating factor (GM-CSF)
• nerve growth factor (NGF)
• neurotrophins
• erythropoietin (EPO)
• thrombopoietin (TPO)
• myostatin (GDF-8)
• Growth Differentiation factor-9 (GDF9)

References

1. ^ Stegmann, T.J.: A human growth factor in the induction of neoangiogenesis. Exp.Opin.Invest.Drugs 7: 2011-2015, 1998
2. ^ Finklestein S.P. and Plomaritoglou A. (2001). "Growth factors", in Miller L.P. and Hayes R.L., eds. Co-edited by Newcomb J.K.: Head Trauma: Basic, Preclinical, and Clinical Directions. John Wiley and Sons, Inc. New York, 165-187. ISBN 0471360155. 
3. ^ Blaber, M., DiSalvo, J. Thomas, K.A.: X-ray crystal structure of human acidic fibroblast growth factor. Biochemistry 35: 2086-2094, 1996
4. ^ Ornitz, D.M., Itoh, N.: Fibroblast growth factors. Genome Biol 2: 1-12, 2001
5. ^ Olsen SK, Garbi M. et al (2003). "Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs". J. Biol. Chem. 278 (36): 34226-34236. PMID 12815063.
6. ^ Gospodarowicz D (1974). "Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth". Nature 249 (453): 123-7. PMID 4364816.
7. ^ Arese M, Chen Y. et al (1999). "Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals.". Mol. Biol. Cell 10 (5): 1429-1444. PMID 10233154.
8. ^ Böttcher RT, Niehrs C. (2005). "Fibroblast growth factor signaling during early vertebrate development". Endocr. Rev. 26 (1): 63-77. PMID 15689573.
9. ^ Amaya E, Musci T.J. and Kirschner M.W. (1991). "Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos". Cell 66 (2): 257-270. PMID 1649700.
10. ^ Borland C.Z., Schutzman J.L. and Stern M.J. (2001). "Fibroblast growth factor signaling in Caenorhabditis elegans". Bioessays 23 (12): 1120-1130. PMID 11746231.
11. ^ Coumoul X. and Deng C.X. (2003). "Roles of FGF receptors in mammalian development and congenital diseases". Birth Defects Res C Embryo Today 69 (4): 286-304. PMID 14745970.
12. ^ Sutherland D, Samakovlis C . and Krasnow M.A. (1996). "Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching". Cell 87 (6): 1091-1101. PMID 8978613.