Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation
Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation
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DOI：
10.1038/ncb983
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发表时间：
2003-05-01
影响因子：
21.3
通讯作者：
Dikic, I
中科院分区：
文献类型：
--
作者：
Haglund, K;Sigismund, S;Dikic, I
许多细胞蛋白质通过添加单个泛素或多聚泛素链进行后修饰（1）。其中包括受体酪氨酸激酶（RTK），其经历配体依赖性泛素化（2）。RTK的泛素化已被认为是其在溶酶体中内吞和降解的重要信号（3）;然而，目前尚不清楚泛素化本身是否足以进行此过程或仅参与其调节。这个问题进一步复杂化的事实是，RTK被认为是多聚泛素化的-一种与蛋白酶体降解蛋白质有关的修饰（4）。相比之下，monoubiquitination与多种蛋白酶体非依赖性细胞功能相关，包括细胞内蛋白质运动（5）。在这里，我们表明，表皮生长因子和血小板衍生生长因子受体不是多泛素化，而是monoubiquitinated在多个网站后，其配体诱导的激活。通过使用不同的生物化学和分子遗传学方法，我们表明，一个单一的泛素是足够的受体内化和降解。因此，单泛素化是负责RTK从质膜移动到溶酶体的主要信号。
Many cellular proteins are post-translationally modified by the addition of a single ubiquitin or a polyubiquitin chain(1). Among these are receptor tyrosine kinases (RTKs), which undergo ligand-dependent ubiquitination(2). The ubiquitination of RTKs has become recognized as an important signal for their endocytosis and degradation in the lysosome(3); however, it is not clear whether ubiquitination itself is sufficient for this process or simply participates in its regulation. The issue is further complicated by the fact that RTKs are thought to be polyubiquitinated-a modification that is linked to protein degradation by the proteasome(4). By contrast, monoubiquitination has been associated with diverse proteasome-independent cellular functions including intracellular protein movement(5). Here we show that the epidermal growth factor and platelet-derived growth factor receptors are not polyubiquitinated but rather are monoubiquitinated at multiple sites after their ligand-induced activation. By using different biochemical and molecular genetics approaches, we show that a single ubiquitin is sufficient for both receptor internalization and degradation. Thus, monoubiquitination is the principal signal responsible for the movement of RTKs from the plasma membrane to the lysosome.