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

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 ()
Additional contact information
Kam Yeung: Brown University, Cell Biology and Biochemistry
Thomas Seitz: GSF-Research Centre for Health and Environment, Institute for Clinical Molecular Biology
Shengfeng Li: Cor Therapeutics Inc.
Petra Janosch: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsdon
Brian McFerran: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsdon
Christian Kaiser: GSF-Research Centre for Health and Environment, Institute for Clinical Molecular Biology
Frances Fee: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsdon
Kostas D. Katsanakis: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsdon
David W. Rose: University of California San Diego
Harald Mischak: Franz-Volhard Klinikum, Max Delbrück Centre
John M. Sedivy: Brown University, Cell Biology and Biochemistry
Walter Kolch: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsdon

Nature, 1999, vol. 401, issue 6749, 173-177

Abstract: Abstract Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types1,2. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK module.

Date: 1999
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DOI: 10.1038/43686

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