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Vol. 10, Issue 1, 179-195, January 1999
*Structural Cell Biology Unit, Department of Medical
Anatomy, The Panum Institute, University of Copenhagen, DK-2200
Copenhagen, Denmark;
Accumulated data indicate that endocytosis of the
glycosylphosphatidyl-inositol-anchored protein urokinase
plasminogen activator receptor (uPAR) depends on binding of the ligand
uPA:plasminogen activator inhibitor-1 (PAI-1) and subsequent
interaction with internalization receptors of the low-density
lipoprotein receptor family, which are internalized through
clathrin-coated pits. This interaction is inhibited by
receptor-associated protein (RAP). We show that uPAR with bound
uPA:PAI-1 is capable of entering cells in a clathrin-independent
process. First, HeLaK44A cells expressing mutant dynamin
efficiently internalized uPA:PAI-1 under conditions in which
transferrin endocytosis was blocked. Second, in polarized Madin-Darby
canine kidney (MDCK) cells, which expressed human uPAR apically, the
low basal rate of uPAR ligand endocytosis, which could not be inhibited
by RAP, was increased by forskolin or phorbol ester (phorbol
12-myristate 13-acetate), which selectively up-regulate
clathrin-independent endocytosis from the apical domain of epithelial
cells. Third, in subconfluent nonpolarized MDCK cells, endocytosis of
uPA:PAI-1 was only decreased marginally by RAP. At the ultrastructural
level uPAR was largely excluded from clathrin-coated pits in these
cells and localized in invaginated caveolae only in the presence of
cross-linking antibodies. Interestingly, a larger fraction of uPAR in
nonpolarized relative to polarized MDCK cells was insoluble in Triton
X-100 at 0°C, and by surface labeling with biotin we also show that internalized uPAR was mainly detergent insoluble, suggesting a correlation between association with detergent-resistant membrane microdomains and higher degree of clathrin-independent endocytosis. Furthermore, by cryoimmunogold labeling we show that 5-10% of internalized uPAR in nonpolarized, but not polarized, MDCK cells is
targeted to lysosomes by a mechanism that is regulated by ligand occupancy.
Department of Medical Biochemistry,
University of Århus, DK-8000 Århus, Denmark; and
§Institute for Cancer Research, The Norwegian Radium
Hospital, 0310 Oslo, Norway
Corresponding author. E-mail address:
f.vilhardt{at}mai.ku.dk.
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