MANNOSE 6-PHOSPHATE INSULIN-LIKE GROWTH-FACTOR-II RECEPTOR TARGETS THE UROKINASE RECEPTOR TO LYSOSOMES VIA A NOVEL BINDING INTERACTION/

The urokinase-type plasminogen activator receptor (uPAR) plays an impo rtant role on the cell surface in mediating extracellular degradative processes and formation of active TGF-beta, and in nonproteolytic even ts such as cell adhesion, migration, and transmembrane signaling. We h ave searched for mechanisms that determine the cellular location of uP AR and may participate in its disposal. When using purified receptor p reparations, we find that uPAR binds to the cation-independent, mannos e 6-phosphate/insulin-like growth factor-II (IGF-II) receptor (CIMPR) with an affinity in the low micromolar range, but not to the 46-kD, ca tion-dependent, mannose 6-phosphate receptor (CDMPR). The binding is n ot perturbed by uPA and appears to involve domains DII + DIII of the u PAR protein moiety, but not the glycosylphosphatidylinositol anchor. T he binding occurs at site(s) on the CIMPR different from those engaged in binding of mannose 6-phosphate epitopes or IGF-II. To evaluate the significance of the binding, immunofluorescence and immunoelectron mi croscopy studies were performed in transfected cells, and the results show that wild-type CIMPR, but not CIMPR lacking an intact sorting sig nal, modulates the subcellular distribution of uPAR and is capable of directing it to lysosomes. We conclude that a site within CIMPR, disti nct from its previously known ligand binding sites, binds uPAR and mod ulates its subcellular distribution.