Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the Raf kinase inhibitor protein

被引:301
作者
Yeung, K
Janosch, P
McFerran, B
Rose, DW
Mischak, H
Sedivy, JM
Kolch, W
机构
[1] Beatson Inst Canc Res, CRC Beatson Labs, Glasgow G61 1BD, Lanark, Scotland
[2] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA
[3] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Whittier Diabet Program, La Jolla, CA 92093 USA
[5] Hannover Med Sch, Nephrol Abt, D-0625 Hannover, Germany
关键词
D O I
10.1128/MCB.20.9.3079-3085.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have recently identified the Raf kinase inhibitor protein (RKIP) as a physiological endogenous inhibitor of the Raf-1/MEK/extracellular signal-regulated kinase (ERK) pathway. RKIP interfered with MEK phosphorylation and activation by Raf-1, resulting in the suppression of both Raf-1-induced transformation and AP-1-dependent transcription. Here we report the molecular mechanism of RKIP's inhibitory function. RKIP can form ternary complexes with Raf-1, MEK, and ERK. However, whereas MEK and ERK can simultaneously associate with RKIP, Raf-1 binding to RKIP and that of MEK are mutually exclusive. RKIP is able to dissociate a Raf-1-MEK complex and behaves as a competitive inhibitor of MEK phosphorylation. Mapping of the binding domains showed that MEK and Raf-1 bind to overlapping sites in RKIP, whereas MEK and RKIP associate with different domains in Raf-1, and Raf-1 and RKIP bind to different sites in MEK. Both the Raf-1 and the MEK binding sites in RKIP need to be destroyed in order to relieve RKIP-mediated suppression of the Raf-1/MEK/ERK pathway, indicating that binding of either Raf-1 or MEK is sufficient for inhibition. The properties of RKIP reveal the specific sequestration of interacting components as a novel motif in the cell's repertoire for the regulation of signaling pathways.
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页码:3079 / 3085
页数:7
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