Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins.
The binding of urokinase plaminogen activator (uPA) to its cell surface receptor (uPAR; CD87) promotes cell adhesion by increasing the affinity of the receptor for both vitronectin (VN) and integrins. We provide evidence that plasminogen activator inhibitor (PAI)-1 can detach cells by disrupting uPAR-VN and integrin-VN interactions and that it does so by binding to the uPA present in uPA-uPAR-integrin complexes on the cell surface. The detached cells cannot reattach to VN unless their surface integrins are first activated by treatment with MnCl2. Immunoprecipitation and subcellular fractionation experiments reveal that PAI-1 treatment triggers deactivation and disengagement of uPA-uPAR-integrin complexes and their endocytic clearance by the low density lipoprotein receptor-related protein. Transfection experiments demonstrate that efficient cell detachment by PAI-1 requires an excess of matrix-engaged uPA-uPAR-integrin complexes over free engaged integrins and that changes in this ratio alter the efficacy of PAI-1. Together, these results suggest a VN-independent, uPA-uPAR-dependent mechanism by which PAI-1 induces cell detachment. This pathway may represent a general mechanism, since PAI-1 also can detach cells from fibronectin and type-1 collagen. This novel "deadhesive" activity of PAI-1 toward a variety of cells growing on different extracellular matrices may begin to explain why high PAI-1 levels often are associated with a poor prognosis in human metastatic disease.
Czekay
Ralf-Peter
RP
The Scripps Research Institute, Dept. of Cell Biology, Div. of Vascular Biology, 10550 N. Torrey Pines Rd., VB-3, La Jolla, CA 92037, USA.
Aertgeerts
Kathleen
K
Curriden
Scott A
SA
Loskutoff
David J
DJ
D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis / Q000502:physiology; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism
D024042:Collagen Type I; D005353:Fibronectins; D039564:Integrin alphaV; D016023:Integrins; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin; D014568:Urokinase-Type Plasminogen Activator