VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation
VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation
复制标题
DOI：
10.1038/onc.2008.44
复制
发表时间：
2008-07-03
期刊：
影响因子：
8
通讯作者：
Chen, J.
中科院分区：
文献类型：
--
作者：
Huang, J.;Chen, J.
2型神经纤维瘤病（NF 2）肿瘤抑制基因功能的失活不仅在家族性神经鞘瘤和其他中枢神经系统肿瘤中观察到，而且在与NF 2综合征无关的恶性肿瘤中也观察到，表明NF 2在人类肿瘤发生中具有更广泛的作用。NF 2编码的蛋白Merlin与膜/细胞骨架连接蛋白的Ezrin-Radixin-Moesin家族密切相关，并且已被证明通过抑制细胞外信号调节激酶（ERK）和Rac 1活化来抑制肿瘤生长。有趣的是，血清剥夺已被证明在蛋白质水平上调节梅林，然而，这种情况究竟如何影响梅林仍然难以捉摸。在这项研究中，我们提供的证据表明，Merlin的调控Roc 1-Cullin 4A-DDB 1依赖的方式。血清刺激后，Merlin通过与含WD 40的衔接蛋白VprBP直接相互作用被募集到E3连接酶复合物中。将Merlin加载到E3泛素连接酶复合物中导致其聚泛素化，并因此导致其蛋白酶体介导的降解。一致地，VprBP耗竭消除了Merlin和Roc 1-Cullin 4A-DDB 1的体内相互作用，这导致Merlin稳定并抑制ERK和Rac活化。总之，我们的数据揭示了梅林肿瘤抑制功能的一种新的调节机制。
Inactivation of the neurofibromatosis type 2 ( NF2) tumor suppressor gene function has been observed not only in familial schwannomas and other central nervous system tumors, but also in malignant tumors unrelated to the NF2 syndrome, indicating a broader role of NF2 in human tumorigenesis. The NF2-encoded protein Merlin is closely related to the Ezrin-Radixin-Moesin family of membrane/cytoskeleton linker proteins, and has been demonstrated to suppress tumor growth by inhibiting extracellular signal-regulated kinase ( ERK) and Rac1 activation. Interestingly, serum deprivation has been shown to regulate Merlin at the protein level, however, exactly how such condition affects Merlin remains elusive. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation. Consistently, VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation. Together, our data revealed a novel regulatory mechanism for the tumor suppressor function of Merlin.