Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases
Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases
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DOI：
10.1074/jbc.m513034200
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发表时间：
2006-08-04
影响因子：
4.8
通讯作者：
Yarden, Yosef
中科院分区：
文献类型：
--
作者：
Oved, Shlomo;Mosesson, Yaron;Yarden, Yosef
当泛素附着在表皮生长因子受体（EGFR）上时，泛素作为溶酶体降解的分选信号。在这里，我们证明了EGFR的泛素连接酶，即c-Cbl，也介导泛素样分子Nedd8对受体的修饰。EGF刺激受体类泛素化，从而增强随后的泛素化，以及EGFR的降解分选。位于EGFR酪氨酸激酶结构域中的多个赖氨酸残基作为Nedd8的附着位点。一组网格蛋白涂层相关的泛素结合物也与Nedd8结合，但它们经历泛素化，而不是泛素化。我们讨论了在生长因子激活受体酪氨酸激酶脱敏的过程中泛素化和类化作用的新兴多功能性。
When appended to the epidermal growth factor receptor ( EGFR), ubiquitin serves as a sorting signal for lysosomal degradation. Here we demonstrate that the ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8. EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting of EGFR for degradation. Multiple lysine residues, located within the tyrosine kinase domain of EGFR, serve as attachment sites for Nedd8. A set of clathrin coat-associated binders of ubiquitin also bind Nedd8, but they undergo ubiquitylation, not neddylation. We discuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases.