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ABSTRACT Ras 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 β-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. Access
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Article Open access 31 March 2025 ACCESSION CODES ACCESSIONS BINDPLUS * 312506 * 312507 * 312508 * 312509 REFERENCES * Downward, J. Targeting RAS signalling pathways in cancer therapy.
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1185–1197 (1994). Article CAS Google Scholar Download references ACKNOWLEDGEMENTS We thank M. Oswald, D. Khalil, C. Dimmler, B. Fauler and U. Reichard for excellent technical assistance,
T. Fowler for critical reading of the manuscript and the EURIT team for their help with siRNA validation. M. Selbach is thanked for kindly providing the Ras constructs and S. Lohmann for the
VASP-P157 antibodies. This work was supported by grants from the Bundesministerium für Bildung und Forschung (BMBF) to T.R. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of
Molecular Biology, Max Planck Institute for Infection Biology, Schumannstr. 21/22, Berlin, D-10117, Germany Krishnaraj Rajalingam, Christian Wunder, Yuri Churin, Claudia Sievers & Thomas
Rudel * Microscopy Core Facility, Schumannstr. 21/22, Berlin, D-10117, Germany Volker Brinkmann * Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg,
Versbacher Strasse 5, Würzburg, 97078, Germany Mirko Hekman & Ulf R. Rapp Authors * Krishnaraj Rajalingam View author publications You can also search for this author inPubMed Google
Scholar * Christian Wunder View author publications You can also search for this author inPubMed Google Scholar * Volker Brinkmann View author publications You can also search for this
author inPubMed Google Scholar * Yuri Churin View author publications You can also search for this author inPubMed Google Scholar * Mirko Hekman View author publications You can also search
for this author inPubMed Google Scholar * Claudia Sievers View author publications You can also search for this author inPubMed Google Scholar * Ulf R. Rapp View author publications You can
also search for this author inPubMed Google Scholar * Thomas Rudel View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to
Thomas Rudel. ETHICS DECLARATIONS COMPETING INTERESTS A patent application has been filed. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary figures S1, S2, S3 and S4;
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_et al._ Prohibitin is required for Ras-induced Raf–MEK–ERK activation and epithelial cell migration. _Nat Cell Biol_ 7, 837–843 (2005). https://doi.org/10.1038/ncb1283 Download citation *
Received: 11 May 2005 * Accepted: 28 June 2005 * Published: 24 July 2005 * Issue Date: August 2005 * DOI: https://doi.org/10.1038/ncb1283 SHARE THIS ARTICLE Anyone you share the following
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