Fibroblast Growth Factors: Evolution

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGF receptors) constitute a signalling system conserved throughout animal evolution. Most members of the FGF family signal across adjacent tissue boundaries and are essential for a variety of developmental and physiological processes. One subfamily of vertebrate FGFs, that may have originated in primitive chordates, appears to have evolved novel functions within neurons. Another subfamily of FGFs has acquired hormoneā€like properties, regulating physiological processes in the adult.

Keywords: fibroblast growth factor (FGF); FGF receptor tyrosine kinase (FGFR); endocrine hormone; heparin/heparan sulfate; neurophysiology; klotho

Figure 1.

Phylogenetic tree for the human FGF gene family. Branch lengths (bootstrap values) are proportional to the distances between the taxa. Seven related subfamilies of Fgfs have been identified. Adapted from Kim .

Figure 2.

Structural features of the FGF polypeptide. The N‐terminus of many of the FGFs (3–8, 10, 15, 17–19, 21–23) contain a signal sequence (shaded). The N‐terminus is also subject to alternative splicing in some FGFs (8, 11–14, 17, 18). The N and C‐termini are variable in length. All FGFs contain a core region ‘FGF domain’ which contains conserved amino acid residues that define the FGF family. Amino acid residues present in at least 70% of all human FGFs define the core domain. Highlighted residues are identical or highly conserved among all FGFs. Spaces indicate the maximum number of intervening residues between conserved residues. N‐terminus, pink; FGF domain, blue and C‐terminus, purple.

Figure 3.

Structural features of the FGF receptor. (a) Short form of the FGF receptor expressing immunoglobulin‐like domains II and III. The shaded region in immunoglobulin‐like domain III is subject to alternative splicing. (b) and (c) Full‐length FGF receptor including immunoglobulin‐like domain I (green), II and III. (b) The immunoglobulin‐like domain IIIb splice form (pink) of the FGF receptor is expressed predominantly in epithelial tissues. (c) The immunoglobulin‐like domain IIIc splice form (blue) of the FGF receptor is expressed predominantly in mesenchymal tissues. (d) Genomic representation of alternative splicing events in FGF receptors. Immunoglobulin‐like domain III is encoded by a common exon a, and by alternatively spliced exons b and c. SP, signal peptide; orange box, heparin/heparan sulfate‐binding domain; I, II and III, immunoglobulin‐like domains; S–S, conserved disulphide bonds in the immunoglobulin‐like domains; TM, transmembrane domain; TK, tyrosine kinase domain.

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References

Allen BL, Filla MS and Rapraeger AC (2001) Role of heparan sulfate as a tissue‐specific regulator of FGF‐4 and FGF receptor recognition. Journal of Cell Biology 155: 845–858.

Benet‐Pages A, Orlik P, Strom TM and Lorenz‐Depiereux B (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Human Molecular Genetics 14: 385–390.

Bishop JR, Schuksz M and Esko JD (2007) Heparan sulphate proteoglycans fine‐tune mammalian physiology. Nature 446: 1030–1037.

Coulier F, Pontarotti P, Roubin R et al. (1997) Of worms and men: an evolutionary perspective on the fibroblast growth factor (FGF) and FGF receptor families. Journal of Molecular Evolution 44: 43–56.

Esko JD and Lindahl U (2001) Molecular diversity of heparan sulfate. Journal of Clinical Investigation 108: 169–173.

Goetz R, Beenken A, Ibrahimi OA et al. (2007) Molecular insights into the klotho‐dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Molecular Cell Biology 27: 3417–3428.

Goldfarb M (2001) Signaling by fibroblast growth factors: the inside story. Science's STKE 2001: PE37.

Goldfarb M (2005) Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Reviews 16: 215–220.

Holland PW (1999) Gene duplication: past, present and future. Seminars in Cell and Developmental Biology 10: 541–547.

Houten SM (2006) Homing in on bile acid physiology. Cell Metabolism 4: 423–424.

Huang P and Stern MJ (2005) FGF signaling in flies and worms: more and more relevant to vertebrate biology. Cytokine Growth Factor Reviews 16: 151–158.

Imai KS, Satoh N and Satou Y (2002) Early embryonic expression of FGF4/6/9 gene and its role in the induction of mesenchyme and notochord in Ciona savignyi embryos. Development 129: 1729–1738.

Itoh N and Ornitz DM (2004) Evolution of the Fgf and Fgfr gene families. Trends in Genetics 20: 563–569.

Kim HS (2001) The human FGF gene family: chromosome location and phylogenetic analysis. Cytogenetics and Cell Genetics 93: 131–132.

Kuro‐O M (2006) Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Current Opinion in Nephrology and Hypertension 15: 437–441.

Lin BC, Wang M, Blackmore C and Desnoyers LR (2007) Liver specific activities of FGF19 require KLOTHO beta. Journal of Biological Chemistry 282(37): 27277–27284.

Lin X and Perrimon N (2000) Role of heparan sulfate proteoglycans in cell–cell signaling in Drosophila. Matrix Biology 19: 303–307.

Liu C, Dib‐Hajj SD and Waxman SG (2001) Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin‐resistant sodium channel rNav1.9a (NaN). Journal of Biological Chemistry 276: 18925–18933.

Liu CJ, Dib‐Hajj SD, Renganathan M, Cummins TR and Waxman SG (2003) Modulation of the cardiac sodium channel Na(v)1.5 by fibroblast growth factor homologous factor 1B. Journal of Biological Chemistry 278: 1029–1036.

Lou JY, Laezza F, Gerber BR et al. (2005) Fibroblast growth factor 14 is an intracellular modulator of voltage‐gated sodium channels. Journal of Physiology 569: 179–193.

Lundasen T, Galman C, Angelin B and Rudling M (2006) Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. Journal of Internal Medicine 260: 530–536.

Martin G (2001) Making a vertebrate limb: new players enter from the wings. Bioessays 23: 865–868.

Martin GR (1998) The roles of FGFs in the early development of vertebrate limbs. Genes and Development 12: 1571–1586.

Mohammadi M, Olsen SK and Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Reviews 16: 107–137.

Nagendra HG, Harrington AE and Harmer NJ (2001) Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution. FEBS Letters 501: 51–58.

Naski MC and Ornitz DM (1998) FGF signaling in skeletal development. Frontiers in Bioscience 3: D781–794.

Ogawa Y, Kurosu H, Yamamoto M et al. (2007) BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proceedings of the National Academy of Sciences of the USA 104: 7432–7437.

Olsen SK, Garbi M, Zampieri N et al. (2003) Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. Journal of Biological Chemistry 278: 34226–34236.

Ornitz DM (2000) FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays 22: 108–112.

Ornitz DM and Itoh N (2001) Fibroblast growth factors. Genome Biology 2: REVIEWS3005.

Ornitz DM and Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes and Development 16: 1446–1465.

Popovici C, Roubin R, Coulier F and Birnbaum D (2005) An evolutionary history of the FGF superfamily. Bioessays 27: 849–857.

Reitman ML (2007) FGF21: a missing link in the biology of fasting. Cell Metabolism 5: 405–407.

Satou Y, Imai KS and Satoh N (2002) Fgf genes in the basal chordate Ciona intestinalis. Development Genes and Evolution 212: 432–438.

Schoorlemmer J and Goldfarb M (2001) Fibroblast growth factor homologous factors are intracellular signaling proteins. Current Biology 11: 793–797.

Smallwood PM, Munoz‐Sanjuan I, Tong P et al. (1996) Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development. Proceedings of the National Academy of Sciences of the USA 93: 9850–9857.

Van Swieten JC, Brusse E, De Graaf BM et al. (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. American Journal of Human Genetics 72: 191–199.

Wang Q, Bardgett ME, Wong M et al. (2002) Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35: 25–38.

Yu X and White KE (2005) FGF23 and disorders of phosphate homeostasis. Cytokine Growth Factor Reviews 16: 221–232.

Zhang X, Ibrahimi OA, Olsen SK et al. (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. Journal of Biological Chemistry 281: 15694–15700.

Further Reading

Birnbaum D, Popovici C and Roubin R (2005) A pair as a minimum: the two fibroblast growth factors of the nematode Caenorhabditis elegans. Developmental Dynamics 232: 247–255.

Dailey L, Ambrosetti D, Mansukhani A and Basilico C (2005) Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Reviews 16: 233–247.

Eswarakumar VP, Lax I and Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Reviews 16: 139–149.

Grose R and Dickson C (2005) Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Reviews 16: 179–186.

Ornitz DM (2005) FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Reviews 16: 205–213.

Presta M, Dell'Era P, Mitola S et al. (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Reviews 16: 159–178.

Wilkie AO (2005) Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Reviews 16: 187–203.

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Ornitz, David M(Dec 2007) Fibroblast Growth Factors: Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006134.pub2]