Postsynaptic density 95/discs large/zonus occludens-1 (PDZ) domain-interacting 
motifs, in addition to their well-established roles in protein scaffolding at 
the cell surface, are proposed to act as cis-acting determinants directing the 
molecular sorting of transmembrane cargo from endosomes to the plasma membrane. 
This hypothesis requires the existence of a specific trans-acting PDZ protein 
that mediates the proposed sorting operation in the endosome membrane. Here, we 
show that sorting nexin 27 (SNX27) is required for efficient PDZ-directed 
recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes. SNX27 
mediates this sorting function when expressed at endogenous levels, and its 
recycling activity requires both PDZ domain-dependent recognition of the 
beta(2)AR cytoplasmic tail and Phox homology (PX) domain-dependent association 
with the endosome membrane. These results identify a discrete role of SNX27 in 
PDZ-directed recycling of a physiologically important signaling receptor, and 
extend the concept of cargo-specific molecular sorting in the recycling pathway.