Fig. 3. PAR endocytic sorting. PAR1 displays both constitutive and agonist-induced internalization. Uncleaved PAR1 constitutively cycles between the plasma membrane and an intracellular compartment. The clathrin adaptor AP2, which binds to a tyrosine-based motif in the PAR1 cytoplasmic tail, mediates constitutive internalization. PAR1 is basally ubiquitylated. Agonist-induced internalization of PAR1 requires phosphorylation and ubiquitylation specifies internalization through clathrin-coated pits. The clathrin adaptor that mediates agonist-induced internalization of ubiquitylated PAR1 has not been identified. Internalized PAR1 is sorted from endosomes to lysosomes through a sorting nexin-1 (SNX1)-dependent pathway, which is independent of ubiquitylation and the ESCRT-1 machinery. Arrestins mediate PAR2 internalization. Internalized PAR2 bound to arrestins appear to signal to ERK1/2 from an endocytic compartment. Sorting of PAR2 from endosomes to lysosomes requires ubiquitylation. The sorting mechanism(s) and adaptor proteins that mediate PAR4 internalization and lysosomal sorting are not known, and whether PAR3 redistributes from the cell surface remains to be determined.