title: From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-alpha kinase activity.
abstract: 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.
authors: Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, 1030 Vienna, Austria.
authors: Théodora
authors: T
authors: Niault
authors: Izabela
authors: I
authors: Sobczak
authors: Katrin
authors: K
authors: Meissl
authors: Gregory
authors: G
authors: Weitsman
authors: Daniela
authors: D
authors: Piazzolla
authors: Gabriele
authors: G
authors: Maurer
authors: Florian
authors: F
authors: Kern
authors: Karin
authors: K
authors: Ehrenreiter
authors: Matthias
authors: M
authors: Hamerl
authors: Ismail
authors: I
authors: Moarefi
authors: Thomas
authors: T
authors: Leung
authors: Oliviero
authors: O
authors: Carugo
authors: Tony
authors: T
authors: Ng
authors: Manuela
authors: M
authors: Baccarini
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D004789:Enzyme Activation; D025461:Feedback, Physiological; D051379:Mice; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019908:Proto-Oncogene Proteins c-raf; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases