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Hrs mediates downregulation of multiple signalling receptors in Drosophila

机译:Hrs介导多种信号转导受体的下调 果蝇

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摘要

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-β 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-β 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.
机译:胞吞作用和随后激活的信号受体的溶酶体降解可减弱信号传导。内吞作用还可以通过将受体靶向特定的区室来促进信号传导。调节受体降解的关键步骤是它们的泛素化。 Hrs / Vps27p是一种与内体相关的泛素结合蛋白,可影响受体的分类和降解。果蝇胚胎的hrs突变体显示受体酪氨酸激酶(RTK)信号升高。还提出了Hrs可以作为TGF-β信号转导的积极介体。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区室中积累了多种信号受体:不仅是RTKs(EGFR和PVR),还包括Notch和Hedgehog和Dpp的受体(与TGF-β相关)。 Dpp信令不需要Hrs。取而代之的是,Hrs的丢失会增加Dpp信号传导和I型受体Thickveins(Tkv)的水平。最后,大多数小时依赖性受体更新似乎是配体依赖性的。因此,活性和非活性信号受体均靶向体内降解,并且需要Hrs才能去除它们。

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