title: Isoform-specific interaction of C-RAF with mitochondria.
abstract: 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.
authors: Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, Germany. antoine.galmiche@mail.uni-wuerzburg.de
authors: Antoine
authors: A
authors: Galmiche
authors: Jochen
authors: J
authors: Fueller
authors: Ansgar
authors: A
authors: Santel
authors: Georg
authors: G
authors: Krohne
authors: Ilka
authors: I
authors: Wittig
authors: Anne
authors: A
authors: Doye
authors: Monica
authors: M
authors: Rolando
authors: Gilles
authors: G
authors: Flatau
authors: Emmanuel
authors: E
authors: Lemichez
authors: Ulf R
authors: UR
authors: Rapp
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D018631:ras Proteins / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D019908:Proto-Oncogene Proteins c-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins