Suppression of the ligand-mediated down-regulation of epidermal growth factor receptor by Ymer, a novel tyrosine-phosphorylated and ubiquitinated protein
Suppression of the ligand-mediated down-regulation of epidermal growth factor receptor by Ymer, a novel tyrosine-phosphorylated and ubiquitinated protein
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DOI：
10.1074/jbc.m604184200
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发表时间：
2006-08-25
影响因子：
4.8
通讯作者：
Taniguchi, Hisaaki
中科院分区：
文献类型：
--
作者：
Tashiro, Kyoko;Konishi, Hiroaki;Taniguchi, Hisaaki
在配体介导的生长因子受体下调之前，还存在其他多种因素的参与。特别是，泛素连接酶Cbl在这一事件中起着核心作用。我们最近的磷酸化蛋白质组学研究已经确定了几个对表皮生长因子（EGF）受体的负调控有潜在影响的候选基因。在这些分子中，我们重点表征了一种新的蛋白质Ymer，这是一种酪氨酸磷酸化和泛素化的蛋白质。发现Ymer在EGF刺激下酪氨酸145和146位点被磷酸化，Ymer的赖氨酸129位点被确定为泛素化位点。Ymer有两个基序与泛素（MIU）结构域相互作用，可能作为泛素化EGF受体的结合位点。虽然Ymer和EGF受体以依赖EGF的方式相关联，但它们的相互作用不仅对MIU结构域是必需的，而且对Ymer的酪氨酸磷酸化也是必需的。磷酸化的Ymer主要位于EGF受体的质膜上，并在其内吞和降解中起作用。此外，在COS7细胞中，过表达Ymer可抑制egf介导的活化egf受体的二次修饰。因此，Ymer可能对EGF受体的激活具有竞争性作用。我们的研究结果表明，Ymer作为一种新的EGF受体下调抑制剂，在调节细胞表面膜上EGF受体的数量方面起着至关重要的作用。
The ligand-mediated down-regulation of the growth factor receptors is preceded by the involvement of various other factors. In particular, a ubiquitin ligase, Cbl, plays a central role in this event. Several candidates that have potential effects on the negative control of the epidermal growth factor (EGF) receptor have now been identified by our recent studies in phospho-proteomics. Among these molecules, we focus on characterizing a novel protein, Ymer, which is a tyrosine-phosphorylated and ubiquitinated protein. Ymer is found to be phosphorylated at tyrosine 145 and 146 upon EGF stimulation, and lysine 129 of Ymer has been identified as a ubiquitination site. Ymer has two motifs interacting with the ubiquitin (MIU) domains that might function as a binding site for the ubiquitinated EGF receptor. Although Ymer and EGF receptors are associated in an EGF-dependent manner, their interaction is required not only for MIU domains but also for the tyrosine phosphorylation of Ymer. Phosphorylated Ymer is mainly located at the plasma membrane with EGF receptor and functions in its endocytosis and degradation. Furthermore, EGF-mediated secondary modifications of an activated-EGF receptor are inhibited by overexpressing Ymer in COS7 cells. Therefore, Ymer may have competitive effects on the activation of the EGF receptor. Our findings suggest that Ymer functions as a novel inhibitor for the down-regulation of the EGF receptor and plays a crucial role for regulating the amount of the EGF receptor on the cell surface membrane.