Prohibitin is required for Ras-induced Raf–MEK–ERK activation and epithelial cell migration

Krishnaraj Rajalingam¹, Christian Wunder¹, Volker Brinkmann², Yuri Churin¹, Mirko Hekman³, Claudia Sievers¹, Ulf R. Rapp³ & Thomas Rudel¹

¹  Max Planck Institute for Infection Biology, Department of Molecular Biology, Schumannstr. 21/22, D-10117 Berlin, Germany.

²  Microscopy Core Facility, Schumannstr. 21/22, D-10117 Berlin, Germany.

³  Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.

312506312507312508312509Ras proteins control the signalling pathways that are responsible for normal growth and malignant transformation¹. Raf protein kinases are direct Ras effector proteins that initiate the mitogen-activated protein kinase (MAPK) cascade², which mediates diverse biological functions such as cell growth, survival and differentiation³. Here we show that prohibitin, a ubiquitously expressed and evolutionarily conserved protein⁴ is indispensable for the activation of the Raf–MEK–ERK pathway by Ras. The membrane targeting and activation of C-Raf by Ras needs prohibitin in vivo. In addition, direct interaction with prohibitin is required for C-Raf activation. C-Raf kinase fails to interact with the active Ras induced by epidermal growth factor in the absence of prohibitin. Moreover, in prohibitin-deficient cells the adhesion complex proteins cadherin and -catenin relocalize to the plasma membrane and thereby stabilize adherens junctions. Our data show an unexpected role of prohibitin in the activation of the Ras–Raf signalling pathway and in modulating epithelial cell adhesion and migration.

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