Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling.

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.
Mesh Terms:
Adenosine Triphosphatases, Cell Membrane, DNA-Binding Proteins, Endocytosis, Endosomal Sorting Complexes Required for Transport, Hela Cells, Humans, Membrane Proteins, Mutation, Phosphoproteins, Protein Sorting Signals, Protein Structure, Tertiary, Receptors, Adrenergic, beta-2, Receptors, G-Protein-Coupled, Receptors, Opioid, mu, Repressor Proteins, Signal Transduction, Transcription Factors, Vesicular Transport Proteins
EMBO J.
Date: Jul. 06, 2005
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