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From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity
The activity of Raf-1 and Rok-α 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-...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779248/ https://www.ncbi.nlm.nih.gov/pubmed/19948477 http://dx.doi.org/10.1083/jcb.200906178 |
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author | Niault, Théodora Sobczak, Izabela Meissl, Katrin Weitsman, Gregory Piazzolla, Daniela Maurer, Gabriele Kern, Florian Ehrenreiter, Karin Hamerl, Matthias Moarefi, Ismail Leung, Thomas Carugo, Oliviero Ng, Tony Baccarini, Manuela |
author_facet | Niault, Théodora Sobczak, Izabela Meissl, Katrin Weitsman, Gregory Piazzolla, Daniela Maurer, Gabriele Kern, Florian Ehrenreiter, Karin Hamerl, Matthias Moarefi, Ismail Leung, Thomas Carugo, Oliviero Ng, Tony Baccarini, Manuela |
author_sort | Niault, Théodora |
collection | PubMed |
description | The activity of Raf-1 and Rok-α 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-α, but the underlying mechanism is unknown. In this study, we show that Rok-α inhibition by Raf-1 relies on an intermolecular interaction between the Rok-α kinase domain and the cysteine-rich Raf-1 regulatory domain (Raf-1reg), which is similar to Rok-α's own autoinhibitory region. Thus, Raf-1 mediates Rok-α 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-α–dependent defects of Raf-1–deficient cells. Downstream of Ras and Rho, the Raf-1–Rok-α interaction represents a novel paradigm of pathway cross talk that contributes to tumorigenesis and cell motility. |
format | Text |
id | pubmed-2779248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-27792482010-05-02 From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity Niault, Théodora Sobczak, Izabela Meissl, Katrin Weitsman, Gregory Piazzolla, Daniela Maurer, Gabriele Kern, Florian Ehrenreiter, Karin Hamerl, Matthias Moarefi, Ismail Leung, Thomas Carugo, Oliviero Ng, Tony Baccarini, Manuela J Cell Biol Research Articles The activity of Raf-1 and Rok-α 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-α, but the underlying mechanism is unknown. In this study, we show that Rok-α inhibition by Raf-1 relies on an intermolecular interaction between the Rok-α kinase domain and the cysteine-rich Raf-1 regulatory domain (Raf-1reg), which is similar to Rok-α's own autoinhibitory region. Thus, Raf-1 mediates Rok-α 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-α–dependent defects of Raf-1–deficient cells. Downstream of Ras and Rho, the Raf-1–Rok-α interaction represents a novel paradigm of pathway cross talk that contributes to tumorigenesis and cell motility. The Rockefeller University Press 2009-11-02 /pmc/articles/PMC2779248/ /pubmed/19948477 http://dx.doi.org/10.1083/jcb.200906178 Text en © 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/). |
spellingShingle | Research Articles Niault, Théodora Sobczak, Izabela Meissl, Katrin Weitsman, Gregory Piazzolla, Daniela Maurer, Gabriele Kern, Florian Ehrenreiter, Karin Hamerl, Matthias Moarefi, Ismail Leung, Thomas Carugo, Oliviero Ng, Tony Baccarini, Manuela From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity |
title | From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity |
title_full | From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity |
title_fullStr | From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity |
title_full_unstemmed | From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity |
title_short | From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity |
title_sort | from autoinhibition to inhibition in trans: the raf-1 regulatory domain inhibits rok-α kinase activity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779248/ https://www.ncbi.nlm.nih.gov/pubmed/19948477 http://dx.doi.org/10.1083/jcb.200906178 |
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