title: Functional phylogeny relates LET-756 to fibroblast growth factor 9.
abstract: Fibroblast growth factors (FGFs) are secreted regulatory proteins involved in various developmental processes. In vertebrates, the FGF superfamily comprises 22 members. In non-vertebrates, six FGF genes have been identified in Ciona intestinalis, three in Drosophila melanogaster, and two (let-756 and egl-17) in Caenorhabditis elegans. The core of LET-756 shares a 30-50% sequence identity with the various members of the superfamily. The relationships between vertebrate and non-vertebrate FGFs are not clear. We made chimeric FGFs by replacing the core region of LET-756 by the cores of various mammalian, fly, and worm FGFs. LET-756 deleted in its core region was no longer able to rescue the lethal phenotype of a let-756 null mutant, and only chimeras containing the cores of FGFs 9, 16, and 20 showed rescue capacity. This core contains an internal motif of six amino acid residues (EFISIA) whose deletion or mutation abolished both the rescue activity and FGF secretion in the supernatant of transfected COS-1 cells. Chimera containing the core of C. intestinalis FGF9/16/20, a potential ortholog of FGF9 lacking the complete EFISIA motif, was not able to rescue the lethal phenotype or be secreted. However, the introduction of the EFISIA motif restored both activities. The data show that the EFISIA motif in the core of LET-756 is essential for its biological activity and that FGFs 9, 16, and 20, which contain that motif, are functionally close to LET-756 and may be evolutionary related. This non-classical mode of secretion using an internal motif is conserved throughout evolution.
authors.affiliation: Laboratory of Molecular Oncology, Institut Paoli-Calmettes and UMR599 INSERM, Marseille Cancer Research Institute, Marseille 13009, France.
authors.forename: Cornel
authors.initials: C
authors.lastname: Popovici
authors.forename: Fabien
authors.initials: F
authors.lastname: Conchonaud
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Régine
authors.initials: R
authors.lastname: Roubin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D019143:Evolution, Molecular; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D010802:Phylogeny
chemical_list: D029742:Caenorhabditis elegans Proteins; C110776:Fgf16 protein, rat; D051525:Fibroblast Growth Factor 9; C402375:Let-756 protein, C elegans; D005346:Fibroblast Growth Factors