Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling
Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling
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DOI：
10.1038/sj.emboj.7600688
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发表时间：
2005-07-06
期刊：
影响因子：
11.4
通讯作者：
von Zastrow, M
中科院分区：
文献类型：
--
作者：
Hanyaloglu, AC;McCullagh, E;von Zastrow, M
众所周知，肝细胞生长因子调节的酪氨酸激酶底物 (Hrs) 通过将激活的受体分类到 MVB/溶酶体途径来终止细胞信号传导。在这里，我们确定了 Hrs 在促进内吞信号受体快速再循环到质膜方面的独特作用。 Hrs 的这种功能对于以序列定向方式再循环的受体来说是特异的，与通过大量膜流进行默认再循环相反，并且在几个方面与先前确定的 Hrs/Vps27p 的膜运输功能有区别。特别是，序列定向回收中的 Hrs 功能不需要参与 MVB/溶酶体分选的其他哺乳动物 E 类基因产物，也不需要受体泛素化。突变研究表明，Hrs 的 VHS 结构域在序列定向回收中发挥着重要作用。破坏 Hrs 依赖性循环可防止 β(2)-肾上腺素能受体的功能性重新敏化，从而将这种原型 G 蛋白偶联受体的细胞信号传导时间谱从持续性转变为短暂性。这些研究确定了 Hrs 在货物特异性回收机制中的新功能，这对于控制已知最大的信号受体家族的功能活性至关重要。
Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is well known to terminate cell signaling by sorting activated receptors to the MVB/lysosomal pathway. Here we identify a distinct role of Hrs in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane. This function of Hrs is specific for receptors that recycle in a sequence-directed manner, in contrast to default recycling by bulk membrane flow, and is distinguishable in several ways from previously identified membrane-trafficking functions of Hrs/Vps27p. In particular, Hrs function in sequence-directed recycling does not require other mammalian Class E gene products involved in MVB/lysosomal sorting, nor is receptor ubiquitination required. Mutational studies suggest that the VHS domain of Hrs plays an important role in sequence-directed recycling. Disrupting Hrs-dependent recycling prevented functional resensitization of the beta(2)-adrenergic receptor, converting the temporal profile of cell signaling by this prototypic G protein-coupled receptor from sustained to transient. These studies identify a novel function of Hrs in a cargo-specific recycling mechanism, which is critical to controlling functional activity of the largest known family of signaling receptors.