Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a mam malian homologue of yeast vacuolar protein sorting (Vps) protein Vps27p; ho wever, the role of Hrs in lysosomal trafficking is unclear. Here, we report that Hrs interacts with sorting nexin 1 (SNX1), a recently identified mamm alian homologue of yeast Vps5p that recognizes the lysosomal targeting code of epidermal growth factor receptor (EGFR) and participates in lysosomal t rafficking of the receptor, Biochemical analyses demonstrate that Hrs and S NX1 are ubiquitous proteins that exist in both cytosolic and membrane-assoc iated pools, and that the association of Hrs and SNX occurs on cellular mem branes but not in the cytosol. Furthermore, endogenous SNX1 and Hrs form a similar to 550-kDa complex that excludes EGFR. Immunofluorescence and subce llular fractionation studies show that Hrs and SNX1 colocalize on early end osomes, By using deletion analysis, we have mapped the binding domains of H rs and SNX1 that mediate their association. Overexpression of Hrs or its SN X1-binding domain inhibits ligand-induced degradation of EGFR, but does not affect either constitutive or ligand-induced receptor-mediated endocytosis . These results suggest that Hrs may regulate lysosomal trafficking through its interaction with SNX1.