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© The Rockefeller University Press, 0021-9525/1998//815 $5.00
The Journal of Cell Biology, Volume 141, Number 3, , 1998 815-828

Articles

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



Anders Nykjær*, Erik I. Christensen{ddagger}, Henrik Vorum*, Henrik Hager*, Claus M. Petersen*, Hans Røigaard*, Hye Y. Min§, Frederik Vilhardt||, Lisbeth B. Møller, Stuart Kornfeld**, and Jørgen Gliemann*

* Department of Medical Biochemistry, {ddagger} Department of Cell Biology, University of Aarhus, DK-8000 Aarhus, Denmark; § Chiron Corporation, Emeryville, California; || Department of Anatomy, Panum Institute, University of Copenhagen, Denmark; John F. Kennedy Institute, Copenhagen, Denmark; and ** Division of Hematology-Oncology, Washington University, St. Louis, Missouri

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 glycosylphosphatidylinositol 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.

Abbreviations used in this paper: Asp-N, asparaginase-N; CDMPR, cation-dependent mannose 6-phosphate receptor; CIMPR, cation-independent mannose 6-phosphate/insulin-like growth factor–II receptor; DTSSP, 3,3-dithiobis(sulfosuccinimidylproprionate); Glc-6-P, glucose 6-phosphate; GPI, glycosylphosphatidylinositol; IGF-II, insulin-like growth factor–II; LAMP-1 and -2, lysosomal associated membrane protein 1 and 2; LDL, low density lipoprotein; LRP, LDL receptor–related protein; Man-6-P, mannose 6-phosphate; m-uPAR, mouse uPAR; PiPLC, phosphoinositol-specific phospholipase C; RAP, receptor-associated protein; TGF-β, transforming growth factor–β; uPAR, urokinase-type plasminogen activator receptor.

Address all correspondence to Anders Nykjær, Department of Medical Biochemistry, University of Aarhus, Ole Worms Allé, Bldg. 170, DK-8000 Aarhus C, Denmark. Tel.: +45 89422884. Fax: +45 86131160. E-mail: an{at}biokemi.aau.dk


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