Hanyaloglu Aylin C, McCullagh Emma, von Zastrow Mark
University of California, San Francisco, CA 94143-2140, USA.
EMBO J. 2005 Jul 6;24(13):2265-83. doi: 10.1038/sj.emboj.7600688. Epub 2005 Jun 9.
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.
肝细胞生长因子调节的酪氨酸激酶底物（Hrs）通过将活化受体分选至多泡体/溶酶体途径来终止细胞信号传导，这一点广为人知。在此，我们确定了Hrs在促进内吞的信号受体快速循环至质膜方面的独特作用。Hrs的这一功能对于以序列定向方式循环的受体具有特异性，这与通过整体膜流进行的默认循环不同，并且在几个方面与先前确定的Hrs/Vps27p的膜运输功能有所区别。特别是，Hrs在序列定向循环中的功能不需要参与多泡体/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结构域在序列定向循环中起重要作用。破坏依赖Hrs的循环会阻止β₂ - 肾上腺素能受体的功能性再敏化，使这种典型的G蛋白偶联受体的细胞信号传导时间模式从持续变为短暂。这些研究确定了Hrs在一种货物特异性循环机制中的新功能，这对于控制最大的已知信号受体家族的功能活性至关重要。
