Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization
Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization
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DOI：
10.1016/j.molcel.2005.10.022
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发表时间：
2005-12-22
期刊：
影响因子：
16
通讯作者：
Marais, R
中科院分区：
文献类型：
--
作者：
Garnett, MJ;Rana, S;Marais, R
蛋白激酶B-RAF在大约7%的人类癌症中突变。大多数突变都是激活的，但令人惊讶的是，少数突变降低了激酶活性。然而，后者仍然可以通过MEK-ERK途径刺激细胞信号传导，因为它们激活相关的家族成员C-RAF。我们研究了B-RAF激活C-RAF的机制。我们发现，C-RAF在胞质溶胶中以RAS独立的方式被激活，这需要激活片段磷酸化和14-3-3与C-RAF的结合。我们发现，野生型B-RAF形成一个复杂的C-RAF在RAS依赖的方式，而突变体结合独立的RAS。重要的是，我们发现野生型B-RAF也可以激活C-RAF。我们的数据表明，B-RAF激活C-RAF通过一种机制，涉及14-3-3介导的异源寡聚化和C-RAF转磷酸化。因此，我们已经鉴定了S-RAF-C-RAF-MEK-ERK级联，其不仅在癌症中而且在正常细胞中发出信号。
The protein kinase B-RAF is mutated in approximately 7% of human cancers. Most mutations are activating, but, surprisingly, a small number have reduced kinase activity. However, the latter can still stimulate cellular signaling through the MEK-ERK pathway because they activate the related family member C-RAF. We examine the mechanism underlying C-RAF activation by B-RAF. We show that C-RAF is activated in the cytosol in a RAS-independent manner that requires activation segment phosphorylation and binding of 14-3-3 to C-RAF. We show that wild-type B-RAF forms a complex with C-RAF in a RAS-dependent manner, whereas the mutants bind independently of RAS. Importantly, we show that wild-type B-RAF can also activate C-RAF. Our data suggest that B-RAF activates C-RAF through a mechanism involving 14-3-3 mediated heterooligomerization and C-RAF transphosphorylation. Thus, we have identified a S-RAF-C-RAF-MEK-ERK cascade that signals not only in cancer but also in normal cells.