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J. Cell Biol.,
Volume 141, Number 3, May 4, 1998 815-828
* Department of Medical Biochemistry, 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- 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
, 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.
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