Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins

doi:10.1083/jcb.200208117

Published 3 March 2003. doi:10.1083/jcb.200208117

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© The Rockefeller University Press, 0021-9525/2003/3/781 $5.00
The Journal of Cell Biology, Volume 160, Number 5, 781-791

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

The Scripps Research Institute, Department of Cell Biology, Division of Vascular Biology, 10550 N. Torrey Pines Road, VB-3, La Jolla, CA 92037

Address correspondence to David J. Loskutoff, The Scripps Research Institute, Dept. of Cell Biology, Div. of Vascular Biology, 10550 N. Torrey Pines Rd., VB-3, La Jolla, CA 92037. Tel.: (858) 784-7125. Fax: (858) 784-7353. E-mail: loskutof{at}scripps.edu

The binding of urokinase plaminogen activator (uPA) to its cellsurface receptor (uPAR; CD87) promotes cell adhesion by increasingthe affinity of the receptor for both vitronectin (VN) and integrins.We provide evidence that plasminogen activator inhibitor (PAI)-1can detach cells by disrupting uPAR–VN and integrin–VNinteractions and that it does so by binding to the uPA presentin uPA–uPAR–integrin complexes on the cell surface.The detached cells cannot reattach to VN unless their surfaceintegrins are first activated by treatment with MnCl₂. Immunoprecipitationand subcellular fractionation experiments reveal that PAI-1treatment triggers deactivation and disengagement of uPA–uPAR–integrincomplexes and their endocytic clearance by the low density lipoproteinreceptor–related protein. Transfection experiments demonstratethat efficient cell detachment by PAI-1 requires an excess ofmatrix-engaged uPA–uPAR–integrin complexes overfree engaged integrins and that changes in this ratio alterthe efficacy of PAI-1. Together, these results suggest a VN-independent,uPA–uPAR-dependent mechanism by which PAI-1 induces celldetachment. This pathway may represent a general mechanism,since PAI-1 also can detach cells from fibronectin and type-1collagen. This novel "deadhesive" activity of PAI-1 toward avariety of cells growing on different extracellular matricesmay begin to explain why high PAI-1 levels often are associatedwith a poor prognosis in human metastatic disease.

Key Words: uPAR (CD87); vitronectin; fibronectin; integrin deactivation; endocytosis

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