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J. Biol. Chem., Vol. 278, Issue 51, 51911-51919, December 19, 2003

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Shedding of Membrane Vesicles Mediates Fibroblast Growth Factor-2 Release from Cells^*

Simona Taverna, Giulio Ghersi, Angela Ginestra, Salvatrice Rigogliuso, Sonia Pecorella, Giovanna Alaimo, Francesca Saladino, Vincenza Dolo, Patrizia Dell'Era¶, Antonio Pavan, Giuseppe Pizzolanti||, Paolo Mignatti**, Marco Presta¶, and Maria Letizia Vittorelli

From the Dipartimento Biologia Cellulare e dello Sviluppo, Università di Palermo, Palermo 90128, Italy, Dipartimento Medicina Sperimentale Università di L'Aquila, L'Aquila 67100, Italy, ^¶Dipartimento Scienze Biomediche e Biotecnologie, Università di Brescia, Brescia 25123, Italy, ^||Cattedra di Endocrinologia, Istituto di Clinica Medica, Policlinico di Palermo, Palermo 90128, Italy, ^**Departments of Surgery and Cell Biology, New York University School of Medicine, New York, New York 10016, and Centro di OncoBiologia Sperimentale, Viale delle Scienze, Palermo 90128, Italy

Fibroblast growth factor-2 (FGF-2), a polypeptide with regulatory activity on cell growth and differentiation, lacks a conventional secretory signal sequence, and its mechanism of release from cells remains unclear. We characterized the role of extracellular vesicle shedding in FGF-2 release. Viable cells released membrane vesicles in the presence of serum. However, in serum-free medium vesicle shedding was dramatically down-regulated, and the cells did not release FGF-2 activity into their conditioned medium. Addition of serum to serum-starved cells rapidly induced intracellular FGF-2 clustering under the plasma membrane and into granules that colocalized with patches of the cell membrane with typical features of shed vesicle membranes. Shed vesicles carried three FGF-2 isoforms (18, 22, 24 kDa). Addition of vesicles to endothelial cells stimulated chemotaxis and urokinase plasminogen activator production, which were blocked by anti-FGF-2 antibodies. Treatment of intact vesicles with 2.0 M NaCl or heparinase, which release FGF-2 from membrane-bound proteoglycans, did not abolish their stimulatory effect on endothelial cells, indicating that FGF-2 is carried inside vesicles. The comparison of the stimulatory effects of shed vesicles and vesicle-free conditioned medium showed that vesicles represent a major reservoir of FGF-2. Thus, FGF-2 can be released from cells through vesicle shedding.

Received for publication, April 22, 2003 , and in revised form, September 26, 2003.

^* This work was supported in part by grants from the Italian Association for Cancer Research (to M. L. V. and M. P.), by Ministero del lavoro e previdenza sociale N.792 (to A. P.), and by the Italian Ministry of University and Scientific and Technological Research (to M. L. V., M. P., and A. P.). 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.

To whom correspondence should be addressed. Tel.: 39-091-6577407; Fax: 39-091-6577430; E-mail: mlvitt{at}unipa.it.

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