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

Item Type:Article
Title:Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP
Creators Name:Yeung, K. and Seitz, T. and Li, S.F. and Janosch, P. and McFerran, B. and Kaiser, C. and Fee, F. and Katsanakis, K.D. and Rose, D.W. and Mischak, H. and Sedivy, J.M. and Kolch, W.
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 types. 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.
Keywords:3T3 Cells, Androgen-Binding Protein, COS Cells, Calcium-Calmodulin-Dependent Protein Kinases, Carrier Proteins, Enzyme Activation, Enzyme Inhibitors, Gene Expression Regulation, Green Fluorescent Proteins, Luminescent Proteins, MAP Kinase Kinase Kinase 1, Molecular Cloning, Neoplastic Cell Transformation, Phosphatidylethanolamine Binding Protein, Phospholipid Transfer Proteins, Prostatein, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins C-Raf, Recombinant Proteins, Secretoglobins, Signal Transduction, Transcription Factor AP-1, Uteroglobin, Animals, Mice, Rats
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Volume:401
Number:6749
Page Range:173-177
Date:9 September 1999
Official Publication:https://doi.org/10.1038/43686
PubMed:View item in PubMed

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