The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase
The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase
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DOI：
10.1126/science.286.5438.309
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发表时间：
1999-10-08
期刊：
影响因子：
56.9
通讯作者：
Liu, YC
中科院分区：
文献类型：
--
作者：
Joazeiro, CAP;Wing, SS;Liu, YC
受体蛋白酪氨酸激酶（RPTKs）的泛素化通过标记活性受体的降解来终止信号传导。c-Cbl是RPTK的一种适配器蛋白，通过其SRC同源性变异2 （SH2）和环指结构域正向调节RPTK泛素化。泛素蛋白连接酶（或E3s）是泛素化途径的组成部分，可识别目标底物并促进其与泛素的连接。c-Cbl蛋白作为E3，可以通过其SH2结构域识别酪氨酸磷酸化的底物，如活化的血小板来源的生长因子受体，并通过其RING结构域招募和变构激活E2泛素偶联酶。这些结果揭示了含有sh2的蛋白作为泛素蛋白连接酶的功能，从而为泛素系统中的底物靶向提供了一种独特的机制。
Ubiquitination of receptor protein-tyrosine kinases (RPTKs) terminates signaling by marking active receptors for degradation. c-Cbl, an adapter protein for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC homology 2 (SH2) and RING finger domains. Ubiquitin-protein Ligases (or E3s) are the components of ubiquitination pathways that recognize target substrates and promote their Ligation to ubiquitin. The c-Cbl protein acted as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain. These results reveal an SH2-containing protein that functions as a ubiquitin-protein Ligase and thus provide a distinct mechanism for substrate targeting in the ubiquitin system.