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.
Hanyaloglu
Aylin C
AC
University of California, San Francisco, CA 94143-2140, USA.
McCullagh
Emma
E
von Zastrow
Mark
M
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases; D033921:Vesicular Transport Proteins; D000099177:Tsg101 Protein
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D010750:Phosphoproteins; D021382:Protein Sorting Signals; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; D012097:Repressor Proteins; D014157:Transcription Factors; D025262:Vacuolar Proton-Translocating ATPases; D033921:Vesicular Transport Proteins; D000099177:Tsg101 Protein; C093846:early endosome antigen 1; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C490305:VPS4A protein, human