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Research Article Free access | 10.1172/JCI119521

Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin.

D A Waltz, L R Natkin, R M Fujita, Y Wei, and H A Chapman

Division of Respiratory Diseases, Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. waltz@a1.tch.harvard.edu

Find articles by Waltz, D. in: JCI | PubMed | Google Scholar

Division of Respiratory Diseases, Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. waltz@a1.tch.harvard.edu

Find articles by Natkin, L. in: JCI | PubMed | Google Scholar

Division of Respiratory Diseases, Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. waltz@a1.tch.harvard.edu

Find articles by Fujita, R. in: JCI | PubMed | Google Scholar

Division of Respiratory Diseases, Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. waltz@a1.tch.harvard.edu

Find articles by Wei, Y. in: JCI | PubMed | Google Scholar

Division of Respiratory Diseases, Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. waltz@a1.tch.harvard.edu

Find articles by Chapman, H. in: JCI | PubMed | Google Scholar

Published July 1, 1997 - More info

Published in Volume 100, Issue 1 on July 1, 1997
J Clin Invest. 1997;100(1):58–67. https://doi.org/10.1172/JCI119521.
© 1997 The American Society for Clinical Investigation
Published July 1, 1997 - Version history
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Abstract

The urokinase receptor (uPAR) coordinates plasmin-mediated cell-surface proteolysis and promotes cellular adhesion via a binding site for vitronectin on uPAR. Because vitronectin also binds plasminogen activator inhibitor type 1 (PAI-1), and plasmin cleavage of vitronectin reduces PAI-1 binding, we explored the effects of plasmin and PAI-1 on the interaction between uPAR and vitronectin. PAI-1 blocked cellular binding of and adhesion to vitronectin by over 80% (IC50 approximately 5 nM), promoted detachment of uPAR-bearing cells from vitronectin, and increased cellular migration on vitronectin. Limited cleavage of vitronectin by plasmin also abolished cellular binding and adhesion and induced cellular detachment. A series of peptides surrounding a plasmin cleavage site (arginine 361) near the carboxy-terminal end of vitronectin were synthesized. Two peptides spanning res 364-380 blocked binding of uPAR to vitronectin (IC50 approximately 8-25 microM) identifying this region as an important site of uPAR-vitronectin interaction. These data illuminate a complex regulatory scheme for uPAR-dependent cellular adhesion to vitronectin: Active urokinase promotes adhesion and also subsequent detachment through activation of plasmin or complex formation with PAI-1. Excess PAI-1 may also promote migration by blocking cellular adhesion and/or promoting detachment, possibly accounting in part for the strong correlation between PAI-1 expression and tumor cell metastasis.

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