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A more recent version of this article appeared on June 1, 2002
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Submitted on November 28, 2001
Revised on February 28, 2002
Accepted on March 18, 2002
1 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7365
2 Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7365
3 National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-5460
* Corresponding author. E-mail address: joann_trejo{at}med.unc.edu.
Degradation or "down-regulation" of protease-activated receptor-1 (PAR1), a G protein-coupled receptor for thrombin, is critical for termination of receptor signaling. Towards understanding the molecular mechanisms by which activated PAR1 is internalized, sorted to lysosomes and degraded we investigated whether PAR1 interacted with sorting nexin 1 (SNX1). SNX1 is a membrane-associated protein that functions in lysosomal sorting of the epidermal growth factor receptor (EGF-R). In vitro biochemical binding assays revealed a specific interaction between a GST fusion of SNX1 and PAR1. In HeLa cells, activated PAR1 co-localized with endogenous SNX1 and robustly co-immunoprecipitated SNX1. SNX1 contains a phox homology (PX) domain predicted to bind phosphatidylinositol-3-phosphate (PtdIns(3)P) and a C-terminal coiled-coil region. To assess SNX1 function we examined the effects of SNX1 deletion mutants on PAR1 trafficking. Neither the N-terminus nor PX domain of SNX1 affected PAR1 trafficking. By contrast, overexpression of SNX1 C-terminus markedly inhibited agonist-induced degradation of PAR1, whereas internalization remained virtually intact. Immunofluorescence microscopy studies revealed substantial PAR1 accumulation in EEA1-positive early endosomes in agonist treated cells expressing SNX1 C-terminus. By contrast, lysosome-associated membrane protein-1 (lamp1) distribution was unperturbed. Together these findings strongly suggest a role for SNX1 in sorting of PAR1 from early endosomes to lysosomes. Moreover, this study provides the first example of a protein involved in lysosomal sorting of a GPCR in mammalian cells.
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