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Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling
Author(s) -
Hanyaloglu Aylin C,
McCullagh Emma,
von Zastrow Mark
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600688
Subject(s) - biology , microbiology and biotechnology , receptor , signal transduction , function (biology) , cell signaling , cell surface receptor , biochemistry
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 β 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.