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J. Biol. Chem., Vol. 283, Issue 21, 14857-14866, May 23, 2008

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Isoform-specific Interaction of C-RAF with Mitochondria^*

Antoine Galmiche¹², Jochen Fueller¹, Ansgar Santel, Georg Krohne^¶, Ilka Wittig^||, Anne Doye^**, Monica Rolando^**, Gilles Flatau^**, Emmanuel Lemichez^**, and Ulf R. Rapp

From the Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Versbacher Strasse 5, D-97078, Würzburg, Germany, Silence Therapeutics AG, Robert Rössle Strasse 10, D-13125, Berlin, Germany, ^¶Division of Electron Microscopy, Biocenter of the University of Würzburg, Am Hubland, D-97074 Würzburg, Germany, ^||Zentrum der Biologischen Chemie, Molekulare Bioenergetik, Universitatsklinikum Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany, ^**INSERM U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Toxines, Microbiennes dans la relation hote pathogènes, Nice, F-06204 Cedex 3, France, Université de Nice Sophia-Antipolis, UFR Medecine, Nice F-06204, France, and Centre Hospitalier Universitaire de Nice, Service de Bactériologie, Hopital Archet 2, Nice F-06204, France

The proteins of the RAF family (A-RAF, B-RAF, and C-RAF) are serine/threonine kinases that play important roles in development, mature cell regulation, and cancer. Although it is widely held that their localization on membranes is an important aspect of their function, there are few data that address this aspect of their mode of action. Here, we report that each member of the RAF family exhibits a specific distribution at the level of cellular membranes and that C-RAF is the only isoform that directly targets mitochondria. We found that the RAF kinases exhibit intrinsic differences in terms of mitochondrial affinity and that C-RAF is the only isoform that binds this organelle efficiently. This affinity is conferred by the C-RAF amino-terminal domain and does not depend on the presence of RAS GTPases on the surface of mitochondria. Finally, we analyzed the consequences of C-RAF activation on mitochondria and observed that this event dramatically changes their morphology and their subcellular distribution. Our observations indicate that: (i) RAF kinases exhibit different localizations at the level of cellular membranes; (ii) C-RAF is the only isoform that directly binds mitochondria; and (iii) through its functional coupling with MEK, C-RAF regulates the shape and the cellular distribution of mitochondria.

Received for publication, November 6, 2007 , and in revised form, February 14, 2008.

^* This work was supported by the Deutsche Forschungsgemeinschaft (German-French Graduate College GRK 1141/1). 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 "Materials and Methods," Figs. 1-10, and Movies 1 and 2.

¹ These authors share first co-authorship.

² To whom correspondence should be addressed. Tel.: 49-931-201-45869; Fax: 49-931-201-45835; E-mail: antoine.galmiche{at}mail.uni-wuerzburg.de.

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