From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity
| Autor: | Katrin Meissl, Gabriele Maurer, Florian Kern, Ismail Moarefi, Izabela Sobczak, Daniela Piazzolla, Oliviero Carugo, Karin Ehrenreiter, Matthias Hamerl, Tony Ng, Thomas Leung, Manuela Baccarini, Gregory Weitsman, Theodora Niault |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
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Physiological rho-Associated Kinases Kinase Guanosine Cell Biology Biology SH3 domain Cell biology Protein Structure Tertiary Enzyme Activation Proto-Oncogene Proteins c-raf chemistry.chemical_compound Enzyme activator Mice chemistry Protein kinase domain Cell Movement Report Animals c-Raf Kinase activity Research Articles Cells Cultured |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | The mechanism by which Raf-1 antagonizes Rok-α to promote migration and tumorigenesis is revealed. 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. |
| Databáze: | OpenAIRE |
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