Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase
Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase
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DOI：
10.1074/jbc.c300542200
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发表时间：
2004-04-16
影响因子：
4.8
通讯作者：
Kariya, K
中科院分区：
文献类型：
--
作者：
Machida, N;Umikawa, M;Kariya, K
Rap 2是Ras家族的一种小GTP结合蛋白，其特异性信号传导作用目前知之甚少。在寻找新的Rap 2相互作用的蛋白质的酵母双杂交系统，我们分离的人促分裂原活化蛋白激酶4（MAP 4K 4），以前描述的，但未表征的亚型3。人类和小鼠中的MAP 4K 4的其他同种型分别被称为造血祖细胞激酶（HPK）/生发中心激酶（GCK）样激酶和NCK相互作用激酶。MAP 4K 4属于蛋白激酶的STE 20组并且调节c-Jun N-末端激酶（JNK）。MAP 4K 4通过其C-末端柠檬同源结构域与Rap 2相互作用，但不与Rap 1或Ras相互作用。与Rap 2的相互作用需要Rap 2的完整效应区。MAP 4K 4在体外与GTP结合的Rap 2的相互作用优先于GDP结合的Rap 2。在培养的细胞中，MAP 4K 4与Rap 2共定位，而缺乏香橼同源结构域的突变体MAP 4K 4未能做到这一点。此外，Rap 2增强MAP 4K 4诱导的JNK活化。这些结果表明，MAP 4K 4是Rap 2介导的JNK激活Rap 2的推定效应。
Little is known about the specific signaling roles of Rap2, a Ras family small GTP-binding protein. In a search for novel Rap2-interacting proteins by the yeast two-hybrid system, we isolated isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a previously described but uncharacterized isoform. Other isoforms of MAP4K4 in humans and mice are known as hematopoietic progenitor kinase (HPK)/germinal center kinase (GCK)-like kinase and Nck-interacting kinase, respectively. MAP4K4 belongs to the STE20 group of protein kinases and regulates c-Jun N-terminal kinase (JNK). MAP4K4 interacted with Rap2 through its C-terminal citron homology domain but did not interact with Rap1 or Ras. Interaction with Rap2 required the intact effector region of Rap2. MAP4K4 interacted preferentially with GTP-bound Rap2 over GDP-bound Rap2 in vitro. In cultured cells, MAP4K4 co-localized with Rap2, while a mutant MAP4K4 lacking the citron homology domain failed to do so. Furthermore, Rap2 enhanced MAP4K4-induced activation of JNK. These results suggest that MAP4K4 is a putative effector of Rap2 mediating the activation of JNK by Rap2.