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Vol. 12, Issue 5, 1467-1479, May 2001
and
Departments of *Cellular and Molecular Medicine and
Low-density lipoprotein receptor-related protein (LRP) mediates
internalization of urokinase:plasminogen activator inhibitor complexes
(uPA:PAI-1) and the urokinase receptor (uPAR). Here we investigated
whether direct interaction between uPAR, a
glycosyl-phosphatidylinositol-anchored protein, and
LRP, a transmembrane receptor, is required for clearance of uPA:PAI-1,
regeneration of unoccupied uPAR, activation of plasminogen, and the
ability of HT1080 cells to invade extracellular matrix. We found that
in the absence of uPA:PAI-1, uPAR is randomly distributed along the
plasma membrane, whereas uPA:PAI-1 promotes formation of uPAR-LRP
complexes and initiates redistribution of occupied uPAR to
clathrin-coated pits. uPAR-LRP complexes are endocytosed via
clathrin-coated vesicles and traffic together to early endosomes (EE)
because they can be coimmunoprecipitated from immunoisolated EE, and
internalization is blocked by depletion of intracellular K+. Direct binding of domain 3 (D3) of uPAR to LRP is
required for clearance of uPA-PAI-1-occupied uPAR because
internalization is blocked by incubation with recombinant D3. Moreover,
uPA-dependent plasmin generation and the ability of HT1080 cells to
migrate through Matrigel-coated invasion chambers are also inhibited in the presence of D3. These results demonstrate that GPI-anchored uPAR is
endocytosed by piggybacking on LRP and that direct binding of occupied
uPAR to LRP is essential for internalization of occupied uPAR,
regeneration of unoccupied uPAR, plasmin generation, and invasion and
migration through extracellular matrix.
Pathology University of California, San Diego, La Jolla,
California 92093-0651
Corresponding author. E-mail address:
rpczekay{at}scripps.edu.
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