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 FGF1) promote angiogenesis [Stegmann, T.J.: A human growth factor in the induction of neoangiogenesis. Exp.Opin.Invest.Drugs 7: 2011-2015, 1998] .

Families

In humans, 22 members of the FGF family have been identified all of which are "structurally" related signaling molecules: [cite book | title=Head Trauma: Basic, Preclinical, and Clinical Directions | author=Finklestein S.P. and Plomaritoglou A. | chapter=Growth factors | editor=Miller L.P. and Hayes R.L., eds. Co-edited by Newcomb J.K. | year=2001 | publisher=John Wiley and Sons, Inc. New York | pages=165-187 | isbn=0471360155] [Blaber, M., DiSalvo, J. Thomas, K.A.: X-ray crystal structure of human acidic fibroblast growth factor. Biochemistry 35: 2086-2094, 1996] [Ornitz, D.M., Itoh, N.: Fibroblast growth factors. Genome Biol 2: 1-12, 2001]

* 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. [cite journal |author=Olsen SK, Garbi M. "et al" |title=Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs |journal=J. Biol. Chem. |volume=278 |issue=36 |pages=34226–34236 |year=2003 |pmid=12815063 |doi=10.1074/jbc.M303183200] This group is also known as "iFGF".cite journal |author=Itoh N, Ornitz DM |title=Functional evolutionary history of the mouse Fgf gene family |journal=Dev. Dyn. |volume=237 |issue=1 |pages=18–27 |year=2008 |month=January |pmid=18058912 |doi=10.1002/dvdy.21388 |url=http://dx.doi.org/10.1002/dvdy.21388]

* Members FGF16 through FGF23 are newer and not as well characterized. FGF15 is the mouse ortholog of human FGF19 (hence there is no human FGF15).

* In contrast to the local activity of the other FGFs, FGF15/FGF19, FGF21 and FGF23 have more systemic effects.cite journal |author=Fukumoto S |title=Actions and mode of actions of FGF19 subfamily members |journal=Endocr. J. |volume=55 |issue=1 |pages=23–31 |year=2008 |month=March |pmid=17878606 |doi= |url=http://joi.jlc.jst.go.jp/JST.JSTAGE/endocrj/KR07E-002?from=PubMed]

Receptors

The fibroblast growth factor receptor family has 4 members, FGFR1, FGFR2, FGFR3, and FGFR4. The FGFRs consist of three extracellular immunoglobulin-type domains (D1-D3), a single-span trans-membrane domain and an intracellular split tyrosine kinase domain. FGFs interact with the D2 and D3 domains, with the D3 interactions primarily responsible for ligand-binding specificity (see below). Heparan sulfate binding is mediated through the D3 domain. A short stretch of acidic amino acids located between the D1 and D2 domains has auto-inhibitory functions. This 'acid box' motif interacts with the heparan sulfate binding site to prevent receptor activation in the absence of FGFs.

Alternate mRNA splicing gives rise to 'b' and 'c' variants of FGFRs 1, 2 and 3. Through this mechanism seven different signaling FGFR sub-types can be expressed at the cell surface. Each FGFR binds to a specific subset of the FGFs. Similarly most FGFs can bind to several different FGFR subtypes. FGF1 is sometimes referred to as the 'universal ligand' as it is capable of activating all 7 different FGFRs. In contrast, FGF7 (keratinocyte growth factor, KGF) binds only to FGFR2b (KGFR).

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 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). [cite journal |author=Gospodarowicz D |title=Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth |journal=Nature |volume=249 |issue=453 |pages=123–7 |year=1974 |pmid=4364816 |doi=10.1038/249123a0]

They then further fractionated the extract using acidic and basic pH and isolated two slightly different forms that were named "acidic fibroblast growth factor" (FGF1) and "basic fibroblast growth factor" (FGF2). These proteins had a high degree of amino acid identity but were determined to be distinct mitogens. Human FGF2 occurs in low molecular weight (LMW) and high molecular weight (HMW) isoforms. [cite journal |author=Arese M, Chen Y. "et al" |title=Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals. |journal=Mol. Biol. Cell |volume=10 |issue=5 |pages=1429–1444 |year=1999 |pmid=10233154] LMW FGF2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF2s are nuclear and exert activities through an intracrine mechanism.

Not long after FGF1 and FGF2 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 FGF1 and FGF2 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. FGF1 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, FGF1 and FGF2 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. [cite journal |author=Böttcher RT, Niehrs C. |title=Fibroblast growth factor signaling during early vertebrate development |journal=Endocr. Rev. |volume=26 |issue=1 |pages=63–77 |year=2005 |pmid=15689573 |doi=10.1210/er.2003-0040]

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. [cite journal |author=Amaya E, Musci T.J. and Kirschner M.W. |title=Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos |journal=Cell |volume=66 |issue=2 |pages=257–270 |year=1991 |pmid=1649700 |doi=10.1016/0092-8674(91)90616-7] [cite journal |author=Borland C.Z., Schutzman J.L. and Stern M.J. |title=Fibroblast growth factor signaling in Caenorhabditis elegans |journal=Bioessays |volume=23 |issue=12 |pages=1120–1130 |year=2001 |pmid=11746231 |doi=10.1002/bies.10007] [cite journal |author=Coumoul X. and Deng C.X. |title= Roles of FGF receptors in mammalian development and congenital diseases |journal=Birth Defects Res C Embryo Today |volume=69 |issue=4 |pages=286–304 |year=2003 |pmid=14745970 |doi= 10.1002/bdrc.10025] [cite journal |author=Sutherland D, Samakovlis C . and Krasnow M.A. |title=Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching |journal=Cell |volume=87 |issue=6 |pages=1091–1101 |year=1996 |pmid=8978613 |doi=10.1016/S0092-8674(00)81803-6]

ee 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

External links

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