Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling.
Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling.
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DOI：
10.1038/srep02344
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发表时间：
2013
影响因子：
4.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
An L;Jia W;Yu Y;Zou N;Liang L;Zhao Y;Fan Y;Cheng J;Shi Z;Xu G;Li G;Yang J;Zhang H
RAF激酶家族在RAS到ERK的信号转导过程中起着至关重要的作用。BRAF结构性活性突变与人类癌症的发生有关。然而，BRAF激活的确切分子调控尚不完全清楚。在这里，我们报道，一旦BRAF被结构性活性突变或表皮生长因子(EGF)刺激激活，它就会被Lys63连接的多泛素化修饰在其激活区的赖氨酸578位。用精氨酸(K578R)替代BRAF赖氨酸578可抑制BRAF介导的ERK激活。此外，BRAF K578R突变体的异位表达抑制了MCF7乳腺癌细胞系不依赖锚定的集落形成。我们的研究发现，在BRAF介导的正常和致癌信号中，Lys63连接的多泛素化具有以前未被认识到的调节作用。
The RAF kinase family is essential in mediating signal transduction from RAS to ERK. BRAF constitutively active mutations correlate with human cancer development. However, the precise molecular regulation of BRAF activation is not fully understood. Here we report that BRAF is modified by Lys63-linked polyubiquitination at lysine 578 within its kinase domain once it is activated by gain of constitutively active mutation or epidermal growth factor (EGF) stimulation. Substitution of BRAF lysine 578 with arginine (K578R) inhibited BRAF-mediated ERK activation. Furthermore, ectopic expression of BRAF K578R mutant inhibited anchorage-independent colony formation of MCF7 breast cancer cell line. Our studies have identified a previously unrecognized regulatory role of Lys63-linked polyubiquitination in BRAF-mediated normal and oncogenic signalings.