Fibroblast Growth Factors

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Angiogenesis
Angiogenesis

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 wide vareity of cells and tissues.

Contents

Families

In humans, 22 members of the FGF family have been identified all of which are structurally related signaling molecules:[1][2][3]

  • 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.[4] This group is also known as "iFGF".[5]
  • 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.[6]

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).[7]

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.[8] 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

FGFs are multifunctional proteins with a wide variety of effects; they are most commonly mitogens but also have regulatory, morphological, and endocrine effects. They have been alternately referred to as "pluripotent" growth factors and as "promiscuous" growth factors due to their multiple actions on multiple cell types [9] [10]. Pluripotent refers to the biology concept of being capable of developing into more than one cell type or tissue. Promiscuous refers to the biochemistry and pharmacology concept of how a variety of molecules can bind to and elicit a response from single receptor. In the case of FGF, four receptor subtypes can be activated by more than twenty different FGF ligands. Thus the functions of FGFs in developmental processes include including mesoderm induction, antero-posterior patterning, limb formation, neural induction and brain development, [11] and in mature tissues/systems angiogenesis, keratinocyte organization, and wound healing processes.

FGF is critical during normal development of both vertebrates and invertebrates and any irregularities in their function leads to a range of developmental defects.[12][13][14][15]

One important function of FGF1 and FGF2 is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures. They thus promote angiogenesis, the growth of new blood vessels from the pre-existing vasculature. FGF1 and FGF2 are more potent angiogenic factors than VEGF (vascular endothelial growth factor) or PDGF (platelet-derived growth factor) however [16]

As well as stimulating blood vessel growth, FGFs are important players in wound healing. FGF1 and FGF2 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. FGF7 and FGF10 (also known as Keratinocyte Growth Factors KGF and KGF2, respectively) stimulate the repair of injured skin and mucosal tissues by stimulating the proliferation, migration and differentiation of epithelial cells, and they have direct chemotactic effects on tissue remodeling.

Most FGFs are secreted proteins that bind heparin sulfates and can therefore be caught up in the extracellular matrix of tissues that contain heparan sulfate proteoglycans. This allows them to act locally in a paracrine fashion. However, the FGF19 subfamily (including FGF19, FGF21, and FGF23) which binds less tightly to heparin sulfates can act in an endocrine fashion on far away tissues, such as intestine, liver, kidney, adipose, and bone. For example, FGF19 is produced by intestinal cells but acts on FGFR4-expressing liver cells to downregulate key genes in the bile acid synthase pathway; FGF23 is produced by bone but acts on FGFR1-expressing kidney cells to regulate the synthesis of vitamin D and in turn affect calcium homeostasis.

See also

References

  1. ^ 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. 
  2. ^ Blaber, M., DiSalvo, J. Thomas, K.A.: X-ray crystal structure of human acidic fibroblast growth factor. Biochemistry 35: 2086-2094, 1996
  3. ^ Ornitz, D.M., Itoh, N.: Fibroblast growth factors. Genome Biol 2: 1-12, 2001
  4. ^ 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. doi:10.1074/jbc.M303183200. PMID 12815063. 
  5. ^ Itoh N, Ornitz DM (January 2008). "Functional evolutionary history of the mouse Fgf gene family". Dev. Dyn. 237 (1): 18–27. doi:10.1002/dvdy.21388. PMID 18058912. 
  6. ^ Fukumoto S (March 2008). "Actions and mode of actions of FGF19 subfamily members". Endocr. J. 55 (1): 23–31. PMID 17878606. 
  7. ^ 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. doi:10.1038/249123a0. PMID 4364816. 
  8. ^ 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. 
  9. ^ Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z (1990). "Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis". Cancer Metastasis Rev 9 (3): 203-26. PMID 1705486. 
  10. ^ Green PJ, Walsh FS, Doherty P (1996). "{{{title}}}". Bioessays 18 (8): 639-46. PMID 8760337. 
  11. ^ Böttcher RT, Niehrs C. (2005). "Fibroblast growth factor signaling during early vertebrate development". Endocr. Rev. 26 (1): 63–77. doi:10.1210/er.2003-0040. PMID 15689573. 
  12. ^ 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. doi:10.1016/0092-8674(91)90616-7. PMID 1649700. 
  13. ^ Borland C.Z., Schutzman J.L. and Stern M.J. (2001). "Fibroblast growth factor signaling in Caenorhabditis elegans". Bioessays 23 (12): 1120–1130. doi:10.1002/bies.10007. PMID 11746231. 
  14. ^ 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. doi:10.1002/bdrc.10025. PMID 14745970. 
  15. ^ 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. doi:10.1016/S0092-8674(00)81803-6. PMID 8978613. 
  16. ^ Vlodavsky Cao R, Bråkenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, Leboulch P, Cao Y (2003). "Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2". Nature Med 9 (5): 604-13. doi:10.1038/nm848. PMID 12669032. 

External links

v • d • e
Growth factors
Fibroblast
FGF receptor ligands: 1 (acidic)/2 (basic)/5 · 3/4/6 · KGF (7/10/22) · 8/17/18 · 9/16/20

FGF homologous factors: 11 · 12 · 13 · 14

hormone-like: 19 · 21 · 23
EGF-like domain
TGFβ pathway
TGFβ (1, 2, 3)
Insulin-like
1 · 2
Platelet-derived
A · B · C · D
Vascular endothelial
A · B · C · D · PGF
Other

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