Mannose 6-Phosphate/Insulin-Like Growth Factor-II Receptor Targets the Urokinase Receptor to Lysosomes via a Novel Binding Interaction

• Published in: The Journal of cell biology Vol. 141; no. 3; pp. 815 - 828
• Main Authors: Nykjær, Anders, Christensen, Erik I., Vorum, Henrik, Hager, Henrik, Petersen, Claus M., Røigaard, Hans, Min, Hye Y., Vilhardt, Frederik, Møller, Lisbeth B., Kornfeld, Stuart, Gliemann, Jørgen
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.05.1998; The Rockefeller University Press
• Subjects: Amino Acid Sequence; Animals; Biological Transport; Cell Line; Cell lines; Cell membranes; Cells; Cellular biology; HeLa cells; Humans; L cells; Ligands; Lysosomes; Lysosomes - metabolism; Mannosephosphates - metabolism; Mice; Molecular Sequence Data; Plasminogen activators; Plasminogen Activators - metabolism; Receptor, IGF Type 2 - metabolism; Receptors; Receptors, Cell Surface - metabolism; Receptors, Urokinase Plasminogen Activator; Subcellular Fractions; Tumor Cells, Cultured; Ungulates
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.141.3.815

The urokinase-type plasminogen activator receptor (uPAR) plays an important role on the cell surface in mediating extracellular degradative processes and formation of active TGF-β, and in nonproteolytic events such as cell adhesion, migration, and transmembrane signaling. We have searched for mechanisms that determine the cellular location of uPAR and may participate in its disposal. When using purified receptor preparations, we find that uPAR binds to the cation-independent, mannose 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, cation-dependent, mannose 6-phosphate receptor (CDMPR). The binding is not perturbed by uPA and appears to involve domains DII + DIII of the uPAR protein moiety, but not the glycosylphosphati-dylinositol anchor. The 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 microscopy studies were performed in transfected cells, and the results show that wild-type CIMPR, but not CIMPR lacking an intact sorting signal, modulates the subcellular distribution of uPAR and is capable of directing it to lysosomes. We conclude that a site within CIMPR, distinct from its previously known ligand binding sites, binds uPAR and modulates its subcellular distribution.