title: Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sorting.
abstract: Parathyroid hormone receptors (PTHR) are promptly internalized upon stimulation by activating (PTH[1-84], PTH[1-34]) and non-activating (PTH[7-84], PTH[7-34]) ligands. Here, we characterized the mechanism regulating the sorting of internalized receptors between recycling and degradative pathways. PTHR recycles faster after challenge with PTH(1-34) than with PTH(7-34). PTHR recycling is complete by 2 h after PTH(1-34) stimulation, but incomplete at this time in cells treated with PTH(7-34). The slower and incomplete recycling induced by PTH(7-34) is due to proteasomal degradation. Both PTH(1-34) and PTH(7-34) induced PTHR polyubiquitination. Ubiquitination by PTH(1-34) was transient, whereas receptor ubiquitination after PTH(7-34) was sustained. PTH(1-34), but not PTH(7-34), induced expression of the PTHR-specific deubiquitinating enzyme USP2. Overexpression of USP2 prevented PTH(7-34)-induced PTHR degradation. We conclude that PTH(1-34) promotes coupled PTHR ubiquitination and deubiquitination, whereas PTH(7-34) activates only ubiquitination, thereby leading to PTHR downregulation. These findings may explain PTH resistance in diseases associated with elevated PTH(7-84) levels.
authors: Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Verónica
authors: V
authors: Alonso
authors: Clara E
authors: CE
authors: Magyar
authors: Bin
authors: B
authors: Wang
authors: Alessandro
authors: A
authors: Bisello
authors: Peter A
authors: PA
authors: Friedman
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D010281:Parathyroid Hormone / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D008024:Ligands; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D018016:Receptors, Parathyroid Hormone; C058350:parathyroid hormone (7-34); D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse; D046988:Proteasome Endopeptidase Complex