Loosening the Binds

Abstract

Cells bind to the extracellular matrix to promote adhesion and control cell motility. One of the interactions that promotes adhesion is through integrins and the urokinase plasminogen activator (uPA) bound to its receptor. uPA binding to its receptor promotes cell adhesion through direct interaction with the extracellular matrix and through enhancement of integrin interactions with the extracellular matrix. Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, disrupts these interactions. PAI-1 and the uPA receptor interact with vitronectin through a single domain, and thus, PAI-1 was thought to promote de-adhesion by competitively disrupting the interaction between vitronectin and the uPA receptor. However, this did not explain the mechanism by which PAI-1 could disrupt adhesion on other extracellular matrix proteins. Czekay et al. showed that PAI-1 disrupted integrin and uPA receptor interactions with the extracellular matrix without requiring direct binding of PAI-1 to the extracellular matrix proteins. Using PAI-1 mutants and vitronectin fragments that could not interact with each other, the authors showed that cell detachment only required the interaction of PAI-1 with uPA bound to the uPA receptor and did not require steric blockage of the integrin-vitronectin interaction or competition with the uPA receptor for vitronectin. PAI-1 stimulated the internalization of uPA-uPA receptor-integrin complexes and the ability to reattach required reactivation of the integrins with MnCl2. PAI-1 also promoted detachment of cells from fibronectin and type 1 collagen matrices, despite PAI-1 not having any direct interaction with these extracellular matrix proteins. The ability of PAI-1 to promote de-adhesion to fibronectin or type 1 collagen correlated with the ratio of integrins associated with uPA-uPA receptor complexes to free integrins, which were associating with the extracellular matrix independently of the uPA receptor. These results suggest a mechanism by which PAI-1 can promote cell de-adhesion by blocking integrin-mediated adhesion on various types of extacellular matrix. Furthermore, the concentration of integrins associated with the uPA receptors controls the effectiveness of PAI-1 in promoting de-adhesion. This mechanism of de-adhesion may explain why with high PAI-1 levels are often indicators of poor prognosis in metastatic cancer.R.-P. Czekay, K. Aertgeerts, S. A. Curriden, D. J. Loskutoff, Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J. Cell Biol. 160, 781-791 (2003). [Abstract] [Full Text]