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J. Biol. Chem., Vol. 279, Issue 38, 40146-40152, September 17, 2004

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Functional Phylogeny Relates LET-756 to Fibroblast Growth Factor 9^*

Cornel Popovici, Fabien Conchonaud, Daniel Birnbaum, and Régine Roubin

From the Laboratory of Molecular Oncology, Institut Paoli-Calmettes and UMR599 INSERM, Marseille Cancer Research Institute, Marseille 13009, France

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.

Received for publication, May 25, 2004

^* The work has been supported by INSERM, Institut Paoli-Calmettes, and grants from the Ligue Nationale Contre le Cancer (Label). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

To whom correspondence should be addressed: UMR599 INSERM, 27 Bd. Leï Roure, 13009 Marseille, France. Tel.: 33-4-91-75-84-11; Fax: 33-4-91-26-03-64; E-mail: roubin{at}marseille.inserm.fr.

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