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Published 3 March 2003. doi:10.1083/jcb1605iti4
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© The Rockefeller University Press, 0021-9525/2003/3/625-a $5.00
The Journal of Cell Biology, Volume 160, Number 5, 625-a-625

In This Issue

A protease inhibitor unsticks cells


PAI-1 (yellow) causes integrins (blue) associated with uPAR (red circles) to be recycled.

PAI-1 is unique among protease inhibitors because it binds to the matrix protein vitronectin (VN). PAI-1 binding blocks VN's binding site for the cell surface receptor uPAR and for integrin family members. Czekay et al. (page 781) now show that PAI-1 is also able to detach cells through a less direct approach.

Unlike the direct competition method, PAI-1 also disrupted integrin-mediated adhesion without ever contacting VN. Instead, PAI-1 bound to another uPAR ligand, the protease uPA. Binding of uPA to uPAR causes integrin recruitment into complexes with uPA and uPAR. PAI-1 disrupted adhesion by inactivating these complexes and triggering their endocytosis. Endocytosis required the low density lipoprotein receptor-related protein, but how PAI-1 triggers integrin inactivation has yet to be determined.

Integrins interact with other matrix molecules in addition to VN. So far, the authors have shown that PAI-1 also detaches cells from fibronectin and collagen, again by promoting integrin endocytosis. In each case, cells expressing high levels of uPAR were more susceptible to PAI-1–induced detachment, because more of their surface integrins were complexed with uPAR. This association could explain why a high level of PAI-1 indicates a poor prognosis for many metastatic cancers—unusual for a protease inhibitor, since proteases normally promote cell invasion. {blacksquare}



Nicole LeBrasseur

lebrasn{at}rockefeller.edu


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Related Article

Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins
Ralf-Peter Czekay, Kathleen Aertgeerts, Scott A. Curriden, and David J. Loskutoff
J. Cell Biol. 2003 160: 781-791. [Abstract] [Full Text] [PDF]




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