The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2
The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2
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DOI：
10.1016/s1097-2765(02)00519-1
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发表时间：
2002-05-01
期刊：
影响因子：
16
通讯作者：
Hunter, T
中科院分区：
文献类型：
--
作者：
Lu, ZM;Xu, SC;Hunter, T
ERK 1/2 MAP激酶是细胞信号转导中的重要调节因子，其活性通常通过苏氨酸-酪氨酸磷酸化可逆调节。相反，我们发现应激诱导的ERK 1/2活性通过泛素/蛋白酶体介导的ERK 1/2降解而下调。MEKK 1的PHD结构域是一个RING指状结构，在体外和体内均表现出E3泛素连接酶对ERK 2的活性。此外，MEKK 1激酶活性和ERK 1/2上的对接基序都参与了ERK 1/2泛素化。值得注意的是，表达ERK 2与对接基序突变的细胞对阿糖胞苷诱导的细胞凋亡具有抗性。因此，MEKK 1不仅通过其激酶结构域作为ERK和JNK的上游激活剂，而且通过其PHD结构域作为E3连接酶，为降低ERK 1/2活性提供负调控机制。
ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Moreover, both MEKK1 kinase activity and the docking motif on ERK1/2 were involved in ERK1/2 ubiquitination. Significantly, cells expressing ERK2 with the docking motif mutation were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity.