C-Raf Inhibits MAPK Activation and Transformation by B-RafV600E
C-Raf Inhibits MAPK Activation and Transformation by B-RafV600E
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DOI：
10.1016/j.molcel.2009.10.017
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发表时间：
2009-11-13
期刊：
影响因子：
16
通讯作者：
Tuveson, David A.
中科院分区：
文献类型：
--
作者：
Karreth, Florian A.;DeNicola, Gina M.;Tuveson, David A.
激活B-Raf突变，使MAPK通路失调，通常发生在癌症中。另外的蛋白质是否调节致癌的B-Raf的酶活性是未知的。在这里，我们表明，原癌基因C-Raf矛盾地抑制B-Raf（V600 E）激酶活性，通过形成B-Raf（V600 E）-C-Raf复合物。尽管所有Raf家族成员都与致癌的B-Raf相关，但这种抑制作用对C-Raf是特异性的。事实上，与C-Raf相互作用能力受损的B-Raf（V600 E）同种型表现出升高的致癌潜力。表达B-Raf（V600 E）的人黑素瘤细胞显示降低的C-Raf：B-Raf比率，并且C-Raf的进一步抑制增加MAPK活化和增殖。相反，异位C-Raf表达降低ERK磷酸化和增殖。此外，致癌Ras和索拉非尼均稳定B-Raf（V600 E）-C-Raf复合物，从而削弱MAPK活化。C-Raf对B-Raf（V600 E）介导的MAPK活化的这种抑制功能可以解释B-Raf（V600 E）和致癌Ras突变的共同出现的缺乏，并影响B-Raf（V600 E）驱动的癌症的小分子抑制剂的成功临床开发。
Activating B-Raf mutations that deregulate the MAPK pathway commonly occur in cancer. Whether additional proteins modulate the enzymatic activity of oncogenic B-Raf is unknown. Here we show that the proto-oncogene C-Raf paradoxically inhibits B-Raf(V600E) kinase activity through the formation of B-Raf(V600E)-C-Raf complexes. Although all Raf family members associate with oncogenic B-Raf, this inhibitory effect is specific to C-Raf. Indeed, a B-Raf(V600E) isoform with impaired ability to interact with C-Raf exhibits elevated oncogenic potential. Human melanoma cells expressing B-Raf(V600E) display a reduced C-Raf:B-Raf ratio, and further suppression of C-Raf increases MAPK activation and proliferation. Conversely, ectopic C-Raf expression lowers ERK phosphorylation and proliferation. Moreover, both oncogenic Ras and Sorafenib stabilize B-Raf(V600E)-C-Raf complexes, thereby impairing MAPK activation. This inhibitory function of C-Raf on B-Raf(V600E)-mediated MAPK activation may explain the lack of co-occurrence of B-Raf(V600E) and oncogenic Ras mutations, and influence the successful clinical development of small molecule inhibitors for B-Raf(V600E)-driven cancers.