LOCALIZATION OF FURIN TO THE TRANS-GOLGI NETWORK AND RECYCLING FROM THE CELL-SURFACE INVOLVES SER AND TYR RESIDUES WITHIN THE CYTOPLASMIC DOMAIN

Furin is a membrane-associated endoprotease that catalyzes cleavage of precursor proteins at Arg-X-Lys/Arg-Arg sites. Although, at steady st ate, furin is predominantly found in the trans-Golgi network (TGN), it also cycles between the TGN and the cell surface. Recently, the cytop lasmic tail of furin has been shown to be sufficient for its localizat ion to the TGN. Within the cytoplasmic domain, there are Ser residues, which we now show are sites for phosphorylation by casein kinase II i n vitro, and a Tyr-containing sequence, both of which have been shown to be important for other TGN proteins to localize to this compartment . In the present study, we show by site-directed mutagenesis that thes e residues are important for TGN localization and recycling of furin. Mutation of the Ser residues abrogated the TGN localization. By contra st, mutation of the Tyr residue did not affect the TGN localization bu t impaired the internalization from the plasma membrane. These observa tions suggest that distinct cytoplasmic determinants are responsible f or retention in the TGN and retrieval from the cell surface of furin.