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

Autor(en)

Theodora Niault, Izabela Sobczak, Katrin Meissl, Gregory Weitsman, Daniela Piazzolla, Gabriele Maurer, Florian Kern, Karin Ehrenreiter, Matthias Hamerl, Ismail Moarefi, Thomas Leung, Oliviero Carugo, Tony Ng, Manuela Baccarini

Abstrakt

The activity of Raf-1 and Rok-{alpha} 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-{alpha}, but the underlying mechanism is unknown. In this study, we show that Rok-{alpha} inhibition by Raf-1 relies on an intermolecular interaction between the Rok-{alpha} kinase domain and the cysteine-rich Raf-1 regulatory domain (Raf-1reg), which is similar to Rok-{alpha}'s own autoinhibitory region. Thus, Raf-1 mediates Rok-{alpha} 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-{alpha}¿dependent defects of Raf-1¿deficient cells. Downstream of Ras and Rho, the Raf-1¿Rok-{alpha} interaction represents a novel paradigm of pathway cross talk that contributes to tumorigenesis and cell motility.,

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik, Department für Strukturbiologie und Computational Biology

Externe Organisation(en)

King's College London, CRELUX GmbH, Institute of Molecular and Cell Biology (IMCB)

Journal

The Journal of Cell Biology (JCB)

Band

187

Seiten

335-342

Anzahl der Seiten

8

ISSN

0021-9525

Publikationsdatum

2009

Peer-reviewed

Ja

ÖFOS 2012

106002 Biochemie, 106013 Genetik, 106023 Molekularbiologie, 301114 Zellbiologie

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/from-autoinhibition-to-inhibition-in-trans-the-raf1-regulatory-domain-inhibits-rokalpha-kinase-activity(b08773ef-0b8e-45de-af20-2fa4711f385b).html