期刊
CELLULAR SIGNALLING
卷 20, 期 5, 页码 935-941出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.01.012
关键词
RKIP; Raf signaling pathway; N-region of Raf; PBP motif
类别
资金
- Cancer Research UK Funding Source: Medline
- NIGMS NIH HHS [R01 GM064767, R01 GM64767] Funding Source: Medline
The Raf-MEK-ERK pathway regulates many fundamental biological processes, and its activity is finely tuned at multiple levels. The Raf kinase inhibitory protein (RKIP) is a widely expressed negative modulator of the Raf-MEK-ERK signaling pathway. We have previously shown that RKIP inhibits the phosphorylation of MEK by Raf-1 through interfering with the formation of a kinase-substrate complex by direct binding to both Raf-1 and MEK. Here, we show that the evolutionarily conserved ligand-binding pocket of RKIP is required for its inhibitory activity towards the Raf-1 kinase mediated activation of MEK. Single amino acid substitutions of two of the conserved residues form the base and the wall of the pocket confers a loss-of-function phenotype on RKIP. Loss-of-function RKIP mutants still appear to bind to Raf-1. However the stability of the complexes formed between mutants and the N-region Raf-1 phosphopeptide were drastically reduced. Our results therefore suggest that the RKIP conserved pocket may constitute a novel phosphoamino-acid binding motif and is absolutely required for RKIP function. (C) 2008 Elsevier Inc. All rights reserved.
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