Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

VOL 401 | 9 SEPTEMBER 1999 | Kam Yeung*,†, Thomas Seitz†‡§, Shengfeng Li§, Petra Janosch†, Brian McFerran||, Christian Kaiser‡, Frances Fee‡, Kostas D. Katsanakis‡, David W. Rose†, Harald Mischak‡, John M. Sedivy†† and Walter Kolch††
The study by Kam Yeung et al. describes the identification and characterization of RKIP (Raf kinase inhibitor protein), a Raf-1-interacting protein that inhibits the activation of MEK and ERK kinases. RKIP was isolated using a yeast two-hybrid screen and found to bind to Raf-1, MEK, and ERK but not to Ras. In vitro and in vivo experiments demonstrated that RKIP competitively disrupts the interaction between Raf-1 and MEK, inhibiting MEK phosphorylation by Raf-1. Overexpression of RKIP reduced the activation of MEK and ERK, AP-1-dependent transcription, and Raf-induced transformation. Downregulation of endogenous RKIP by antisense RNA or antibody microinjection activated MEK, ERK, and AP-1-dependent transcription. The authors propose that RKIP functions as a rheostat, regulating the sensitivity threshold for the activation of the Raf/MEK/ERK pathway, which is crucial for various cellular responses such as cell-cycle arrest, transformation, mitogenesis, and differentiation.The study by Kam Yeung et al. describes the identification and characterization of RKIP (Raf kinase inhibitor protein), a Raf-1-interacting protein that inhibits the activation of MEK and ERK kinases. RKIP was isolated using a yeast two-hybrid screen and found to bind to Raf-1, MEK, and ERK but not to Ras. In vitro and in vivo experiments demonstrated that RKIP competitively disrupts the interaction between Raf-1 and MEK, inhibiting MEK phosphorylation by Raf-1. Overexpression of RKIP reduced the activation of MEK and ERK, AP-1-dependent transcription, and Raf-induced transformation. Downregulation of endogenous RKIP by antisense RNA or antibody microinjection activated MEK, ERK, and AP-1-dependent transcription. The authors propose that RKIP functions as a rheostat, regulating the sensitivity threshold for the activation of the Raf/MEK/ERK pathway, which is crucial for various cellular responses such as cell-cycle arrest, transformation, mitogenesis, and differentiation.
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