Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4
Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4
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DOI：
10.1034/j.1600-0854.2002.31006.x
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发表时间：
2002-10-01
期刊：
影响因子：
4.5
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Katz, M;Shtiegman, K;Yarden, Y
表皮生长因子受体（EGFR）的配体依赖内吞作用包括泛素连接酶的募集和泛素化受体的分类，以降解溶酶体。通过研究Hgs，酵母液泡分选受体的哺乳动物同源物，我们提供了鲜为人知的、不依赖于配体的受体内吞和降解途径的信息。构成性内吞作用包括受体泛素化和转运到含hgs的内体。而Hgs的脂质结合基序是受体内吞作用所必需的，泛素相互作用基序负调控受体降解。我们证明了泛素相互作用基序具有两种功能：它结合泛素化蛋白，并通过募集Nedd4靶向自身泛素化，Nedd4是一种泛素连接酶，以前与内吞作用有关。基于泛素相互作用基序的双重功能及其在内吞接头中的广泛存在，我们提出了一个泛素相互作用基序网络，该网络通过连续出芽事件将泛素化膜受体传递到溶酶体降解。
Ligand-dependent endocytosis of the epidermal growth factor receptor (EGFR) involves recruitment of a ubiquitin ligase, and sorting of ubiquitylated receptors to lysosomal degradation. By studying Hgs, a mammalian homolog of a yeast vacuolar-sorting adaptor, we provide information on the less understood, ligand-independent pathway of receptor endocytosis and degradation. Constitutive endocytosis involves receptor ubiquitylation and translocation to Hgs-containing endosomes. Whereas the lipid-binding motif of Hgs is necessary for receptor endocytosis, the ubiquitin-interacting motif negatively regulates receptor degradation. We demonstrate that the ubiquitin-interacting motif is endowed with two functions: it binds ubiquitylated proteins and it targets self-ubiquitylation by recruiting Nedd4, an ubiquitin ligase previously implicated in endocytosis. Based upon the dual function of the ubiquitin-interacting motif and its wide occurrence in endocytic adaptors, we propose a ubiquitin-interacting motif network that relays ubiquitylated membrane receptors to lysosomal degradation through successive budding events.