Fibroblast Growth Factors (FGFs) are small proteins generally secreted, acting through binding to transmembrane tyrosine kinase receptors (FGFRs). Activation of FGFRs triggers several cytoplasmic cascades leading to the modification of cell behavior. FGFs play critical roles in a variety of developmental and physiological processes. Since their discovery in mammals, FGFs have been found in many metazoans and some arthropod viruses. Efforts have been previously made to decipher the evolutionary history of this family but conclusions were limited due to a poor taxonomic coverage. We took advantage of the availability of many new sequences from diverse metazoan lineages to further explore the possible evolutionary scenarios explaining the diversity of the FGF gene family. Our analyses, based on phylogenetics and synteny conservation approaches, allow us to propose a new classification of FGF genes into eight subfamilies, and to draw hypotheses for the evolutionary events leading to the present diversity of this gene family. 1. Introduction Fibroblast growth factors (FGFs) form a family of generally extracellular signaling peptides, which are key regulators of many biological processes ranging from cell proliferation to the control of embryonic development in metazoans. Ever since the mitogenic activity of FGF-like factors was first observed in 1939 [1] and the first FGF factor was isolated in the 1970s [2], a large number of members of this gene family have been isolated and characterized in different metazoans. FGFs are small proteins (between 17 and 34？kDa) characterized by a relatively well conserved central domain of 120 to 130 amino acids. This domain is organized into 12 antiparallel β sheets forming a triangular structure called beta trefoil. In general, FGFs function through binding to a tyrosine kinase receptor (FGFR) on the surface of the cell membrane. Two FGF ligands bind a dimeric receptor in the presence of heparan sulphate proteoglycan (HSPG) allowing the transphosphorylation and activation of the intracellular tyrosine kinase domain of the receptor. Binding to FGFRs usually activates several intracellular cascades (i.e., Ras/MAPK, PI3K/Akt, and PLC /PKC) which may regulate the transcription of different target genes. Through the activation of these cytoplasmic pathways, the FGF signal controls several major cellular functions such as cell proliferation, migration, differentiation, or survival. An intracellular mode of action has also been described in the case of FGF1 but it is poorly documented [3]. Concerning the evolutionary history of
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