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. ▪