Regulation of c-Src tyrosine kinase activity by bengamide a through inbition of methionine aminopeptidases
Regulation of c-Src tyrosine kinase activity by bengamide a through inbition of methionine aminopeptidases
复制标题
DOI：
10.1016/j.chembiol.2007.05.010
复制
发表时间：
2007-07-01
影响因子：
--
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Hu, Xiaoyi;Dang, Yongjun;Liu, Jun O.
甲硫氨酸氨基肽酶(MetAPs)在蛋白质合成过程中去除N-末端的起始物蛋氨酸，这是N-末端肉豆蔻酰化的先决条件。原癌基因c-Src的N-肉豆蔻酰化是其膜结合和正确的信号转导所必需的。我们使用Bengamide，一个通用的Metap抑制剂家族，来了解Metap的下游生理功能。苯乙酰胺A处理细胞的c-Src保留其N-末端蛋氨酸，N-末端肉豆蔻酰化程度降低，同时其亚细胞分布从质膜向胞浆转移。此外，苯酰胺A在体外和体内都降低了c-Src的酪氨酸激酶活性，并最终通过G(2)/M延迟了细胞周期进程。因此，c-Src是Metap的生理相关底物，其功能障碍可能解释了包括苯酰胺A在内的Metap抑制剂对细胞周期的影响。
Methionine aminopeptidases (MetAPs) remove the N-terminal initiator methionine during protein synthesis, a prerequisite step for N-terminal myristoylation. N-myristoylation of protooncogene c-Src is essential for its membrane association and proper signal transduction. We used bengamides, a family of general MetAP inhibitors, to understand the downstream physiological functions of MetAPs. c-Src from bengamide A-treated cells retained its N-terminal methionine and suffered a decrease in N-terminal myristoylation, which was accompanied by a shift of its subcellular distribution from the plasma membrane to the cytosol. Furthermore, bengamide A decreased the tyrosine kinase activities of c-Src both in vitro and in vivo and eventually delayed cell-cycle progression through G(2)/M. Thus, c-Src is a physiologically relevant substrate for MetAPs whose dysfunction is likely to account for the cell-cycle effects of MetAP inhibitors including bengamide A.