The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3
The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3
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DOI：
10.1073/pnas.1510495112
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发表时间：
2015-11-17
影响因子：
11.1
通讯作者：
Mayadas, Tanya N.
中科院分区：
文献类型：
--
作者：
Cullere, Xavier;Plovie, Eva;Mayadas, Tanya N.
三个基因，CCM1，CCM2和CCM3，在遗传和生物化学上相互作用，并在脑海绵状血管畸形（CCM）中发生突变。最近描述的这个CCM蛋白家族的成员，CCM2样（CCM2L），与CCM2具有高度同源性。在这里，我们表明，其在不同组织中的相对表达不同于CCM 2，并且与CCM 2不同，CCM 2L在内皮细胞中的表达受密度、流量和他汀类药物的调节。在体外，CCM2L和CCM2都以与CCM1的复合物结合MEKK 3。CCM2L和CCM2均干扰MEKK3活化及其磷酸化下游靶标MEK5的能力。在斑马鱼中研究了这种调节的体内相关性。与单独的CCM 2功能丧失相比，斑马鱼中CCM 21和CCM 2的敲低导致更严重的“大心脏”和循环缺陷，并且还导致实质性的体轴异常。mekk3的沉默拯救了大心脏和体轴表型，表明CCM蛋白和MEKK3之间的体内串扰。在内皮细胞中，CCM2缺失导致ERK 5的激活和MEKK 3下游的转录程序。这些发现表明CCM2L和CCM2协同调节MEKK3的活性。
Three genes, CCM1, CCM2, and CCM3, interact genetically and biochemically and are mutated in cerebral cavernous malformations (CCM). A recently described member of this CCM family of proteins, CCM2-like (CCM2L), has high homology to CCM2. Here we show that its relative expression in different tissues differs from that of CCM2 and, unlike CCM2, the expression of CCM2L in endothelial cells is regulated by density, flow, and statins. In vitro, both CCM2L and CCM2 bindMEKK3 in a complex with CCM1. Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target. The in vivo relevance of this regulation was investigated in zebrafish. A knockdown of ccm2l and ccm2 in zebrafish leads to a more severe "big heart" and circulation defects compared with loss of function of ccm2 alone, and also leads to substantial body axis abnormalities. Silencing of mekk3 rescues the big heart and body axis phenotype, suggesting cross-talk between the CCM proteins and MEKK3 in vivo. In endothelial cells, CCM2 deletion leads to activation of ERK5 and a transcriptional program that are downstream of MEKK3. These findings suggest that CCM2L and CCM2 cooperate to regulate the activity of MEKK3.