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From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok- kinase activity

¹ Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, 1030 Vienna, Austria
² Richard Dimbleby Department of Cancer Research, ³ Randall Division of Cell and Molecular Biophysics, and ⁴ Division of Cancer Studies, King's College London, WC2R 2LS London, England, UK
⁵ CRELUX GmbH, 82152 Martinsried, Germany
⁶ Institute of Molecular and Cell Biology, Singapore 138673
⁷ Department of General Chemistry, University of Pavia, 27100 Pavia, Italy

Correspondence to Manuela Baccarini: manuela.baccarini{at}univie.ac.at

The activity of Raf-1 and Rok- kinases is regulated by intramolecular binding of the regulatory region to the kinase domain. Autoinhibition is relieved upon binding to the small guanosine triphosphatases Ras and Rho. Downstream of Ras, Raf-1 promotes migration and tumorigenesis by antagonizing Rok-, but the underlying mechanism is unknown. In this study, we show that Rok- inhibition by Raf-1 relies on an intermolecular interaction between the Rok- kinase domain and the cysteine-rich Raf-1 regulatory domain (Raf-1reg), which is similar to Rok-'s own autoinhibitory region. Thus, Raf-1 mediates Rok- inhibition in trans, which is a new concept in kinase regulation. This mechanism is physiologically relevant because Raf-1reg is sufficient to rescue all Rok-–dependent defects of Raf-1–deficient cells. Downstream of Ras and Rho, the Raf-1–Rok- interaction represents a novel paradigm of pathway cross talk that contributes to tumorigenesis and cell motility.

Abbreviations used in this paper: CRD, cysteine-rich domain; ERK, extracellular signal-regulated kinase; FLIM, fluorescent lifetime imaging microscopy; FRET, fluorescence resonance energy transfer; KO, knockout; MEF, mouse embryonic fibroblast; MEK, MAPK/ERK kinase; mRFP, monomeric RFP; PH, pleckstrin homology; Raf-1reg, Raf-1 regulatory domain; Rok-reg, Rok- regulatory domain; RBD, Ras/Rho-binding domain; WT, wild type.

© 2009 Niault et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Short, B. (2009). Raf-1 sheds then spreads its inhibitions. JCB 187: 314-314 [Full Text]  

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