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J. Biol. Chem., Vol. 279, Issue 8, 6244-6251, February 20, 2004

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Unconventional Secretion of Fibroblast Growth Factor 2 Is Mediated by Direct Translocation across the Plasma Membrane of Mammalian Cells

Tobias Schäfer, Hanswalter Zentgraf, Christoph Zehe, Britta Brügger, Jürgen Bernhagen¶, and Walter Nickel||

From the Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, and ^¶Unit of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany

Fibroblast growth factor 2 (FGF-2) is a pro-angiogenic mediator that is secreted by both normal and neoplastic cells. Intriguingly, FGF-2 has been shown to be exported by an endoplasmic reticulum/Golgi-independent pathway; however, the molecular machinery mediating this process has remained elusive. Here we introduce a novel in vitro system that functionally reconstitutes FGF-2 secretion. Based on affinity-purified plasma membrane inside-out vesicles, we demonstrate post-translational membrane translocation of FGF-2 as shown by protease protection experiments. This process is blocked at low temperature but apparently does not appear to be driven by ATP hydrolysis. FGF-2 membrane translocation occurs in a unidirectional fashion requiring both integral and peripheral membrane proteins. These findings provide direct evidence that FGF-2 secretion is based on its direct translocation across the plasma membrane of mammalian cells. When galectin-1 and macrophage migration inhibitory factor, other proteins exported by unconventional means, were analyzed for translocation into plasma membrane inside-out vesicles, galectin-1 was found to be transported as efficiently as FGF-2. By contrast, migration inhibitory factor failed to traverse the membrane of inside-out vesicles. These findings establish the existence of multiple distinct secretory routes that are operational in the absence of a functional endoplasmic reticulum/Golgi system.

Received for publication, September 23, 2003 , and in revised form, November 7, 2003.

^* This work was supported by German Research Foundation Grant DFG Ni 423 and the Ministry of Science, Research, and the Arts of the State of Baden-Württemberg. 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. E-mail: walter.nickel{at}urz.uni-heidelberg.de.

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