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Vol. 13, Issue 6, 1965-1976, June 2002
and
Departments of *Pharmacology and Degradation or "down-regulation" of protease-activated
receptor-1 (PAR1), a G protein-coupled receptor for thrombin, is
critical for termination of receptor signaling. Toward 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. In vitro biochemical binding assays revealed a
specific interaction between a glutathione S-transferase
fusion of SNX1 and PAR1. In HeLa cells, activated PAR1 colocalized with endogenous SNX1 and coimmunoprecipitated SNX1. SNX1 contains a phox
homology domain predicted to bind
phosphatidylinositol-3-phosphate 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 phox
homology domain of SNX1 affected PAR1 trafficking. By contrast,
overexpression of SNX1 C-terminal domain markedly inhibited
agonist-induced degradation of PAR1, whereas internalization remained
virtually intact. Immunofluorescence microscopy studies revealed
substantial PAR1 accumulation in an early endosome antigen-1-positive
compartment in agonist-treated cells expressing SNX1 C terminus. By
contrast, lysosome-associated membrane protein-1 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 G protein-coupled receptor in mammalian cells.
Cell and Molecular
Physiology, School of Medicine, University of North Carolina at Chapel
Hill, North Carolina 27599-7365; and National Institutes
of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, Maryland 20892-5460
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