Fibroblast growth factor
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'''Fibroblast growth factors''', or '''FGFs''', are a family of [[growth factor]]s 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]]<ref>Stegmann, T.J.: A human growth factor in the induction of neoangiogenesis. Exp.Opin.Invest.Drugs 7: 2011-2015, 1998</ref>.
==Families==
In humans, 23 members of the FGF family have been identified all of which are ''structurally'' related [[cell signaling|signaling]] molecules:<ref>{{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}}</ref><ref>Blaber, M., DiSalvo, J. Thomas, K.A.: X-ray crystal structure of human acidic fibroblast growth factor. Biochemistry 35: 2086-2094, 1996</ref><ref>Ornitz, D.M., Itoh, N.: Fibroblast growth factors. Genome Biol 2: 1-12, 2001</ref>
* Members [[FGF1]] through {{Gene|FGF10}} all bind [[fibroblast growth factor receptor]]s (FGFRs). [[FGF1]] is also known as "Acidic", and {{Gene|FGF2}} is also known as [[basic fibroblast growth factor]].
* Members {{Gene|FGF11}}, {{Gene|FGF12}}, {{Gene|FGF13}}, and {{Gene|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 [[FGFR]]s and are involved in intracellular processes unrelated to the FGFs.<ref>{{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}}</ref>
* Members {{Gene|FGF16}} through {{Gene|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 [[fibroblast]]s to [[cell proliferation|proliferate]] (first published report in 1974).<ref>{{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}}</ref>
They then further fractionated the extract using [[acid]]ic and [[base (chemistry)|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.<ref>{{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}}</ref>
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 [[cell proliferation|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 vessel]]s 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.<ref>{{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}}</ref>
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.<ref>{{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}}</ref>
<ref>{{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}}</ref>
<ref>{{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}}</ref>
<ref>{{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}}</ref>
==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==
{{reflist|2}}
==External links==
* {{MeshName|Fibroblast+Growth+Factors}}
{{Signaling proteins}}
[[Category:Growth factors]]
[[Category:Morphogens]]
[[de:Fibroblast growth factor]]