Hrs mediates downregulation of multiple signalling receptors in Drosophila
Hrs mediates downregulation of multiple signalling receptors in Drosophila
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DOI：
10.1038/sj.embor.7400019
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发表时间：
2003-12-01
期刊：
影响因子：
7.7
通讯作者：
Rorth, P
中科院分区：
文献类型：
--
作者：
Jékely, G;Rorth, P
内吞作用和随后激活的信号受体的溶酶体降解可以减弱信号。内吞作用也可能通过将受体靶向到特定的室来促进信号传导。调节受体降解的关键步骤是它们的泛素化。Hrs/Vps27p是一种内体相关的泛素结合蛋白，影响受体的分选和降解。果蝇胚胎突变hrs显示受体酪氨酸激酶（RTK）信号传导升高。Hrs也被认为是tgf - β信号传导的积极介质。我们发现，缺乏Hrs的果蝇上皮细胞在具有高水平泛素化蛋白的内体腔室中积累了多种信号受体：不仅有rtk (EGFR和PVR)，还有Notch和Hedgehog和Dpp受体（tgf - β相关）。Dpp信令不需要Hrs。相反，Hrs的缺失会增加Dpp信号和i型受体粗静脉（Tkv）的水平。最后，大多数依赖于hr的受体转换似乎是与配体无关的。因此，活性和非活性信号受体都是体内降解的目标，并且需要hr来去除它们。
Endocytosis and subsequent lysosomal degradation of activated signalling receptors can attenuate signalling. Endocytosis may also promote signalling by targeting receptors to specific compartments. A key step regulating the degradation of receptors is their ubiquitination. Hrs/Vps27p, an endosome-associated, ubiquitin-binding protein, affects sorting and degradation of receptors. Drosophila embryos mutant for hrs show elevated receptor tyrosine kinase (RTK) signalling. Hrs has also been proposed to act as a positive mediator of TGF-beta signalling. We find that Drosophila epithelial cells devoid of Hrs accumulate multiple signalling receptors in an endosomal compartment with high levels of ubiquitinated proteins: not only RTKs (EGFR and PVR) but also Notch and receptors for Hedgehog and Dpp (TGF-beta related). Hrs is not required for Dpp signalling. Instead, loss of Hrs increases Dpp signalling and the level of the type-I receptor Thickveins (Tkv). Finally, most hrs-dependent receptor turnover appears to be ligand independent. Thus, both active and inactive signalling receptors are targeted for degradation in vivo and Hrs is required for their removal.