Rheb inhibits C-Raf activity and B-Raf/C-Raf heterodimerization
Rheb inhibits C-Raf activity and B-Raf/C-Raf heterodimerization
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DOI：
10.1074/jbc.m605273200
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发表时间：
2006-09-01
影响因子：
4.8
通讯作者：
Henske, Elizabeth Petri
中科院分区：
文献类型：
--
作者：
Karbowniczek, Magdalena;Robertson, Gavin P.;Henske, Elizabeth Petri
Ras-Raf-MEK信号级联对于正常发育至关重要，并在许多形式的癌症中被激活。我们最近发现B-Raf激酶与Rheb相互作用并被Rheb抑制，Rheb是结节性硬化症复合体2基因产物tuberin的gtpase激活域的靶点。在这里，我们首次证明了Rheb的激活与B-Raf和C-Raf分别在Ser-446和Ser-338残基磷酸化降低有关，同时两种激酶的活性降低，B-Raf和C-Raf的异源二聚化减少。重要的是，Rheb对B-Raf/C-Raf异源二聚化和激酶活性的影响是雷帕霉素不敏感的，这表明它们独立于Rheb对雷帕霉素-猛禽复合物的哺乳动物靶点的激活。此外，我们发现Rheb抑制B-Raf与H-Ras的结合。综上所述，这些结果支持Rheb在Ras/B-Raf/C-Raf/MEK信号网络调控中的核心作用。
The Ras-Raf-MEK signaling cascade is critical for normal development and is activated in many forms of cancer. We have recently shown that B-Raf kinase interacts with and is inhibited by Rheb, the target of the GTPase-activating domain of the tuberous sclerosis complex 2 gene product tuberin. Here, we demonstrate for the first time that activation of Rheb is associated with decreased B-Raf and C-Raf phosphorylation at residues Ser-446 and Ser-338, respectively, concomitant with a decrease in the activities of both kinases and decreased heterodimerization of B-Raf and C-Raf. Importantly, the impact of Rheb on B-Raf/C-Raf heterodimerization and kinase activity are rapamycin-insensitive, indicating that they are independent of Rheb activation of the mammalian target of rapamycin-Raptor complex. In addition, we found that Rheb inhibits the association of B-Raf with H-Ras. Taken together, these results support a central role of Rheb in the regulation of the Ras/B-Raf/C-Raf/MEK signaling network.