Abstract
Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily of proteins, circulates in a complex with vitronectin. Furthermore, these two proteins are co-localized in the extracellular matrix (ECM) in many different pathophysiological conditions. Though PAI-1 is a well-characterized inhibitor of serine proteases, recent emphasis has also focused on its protease-independent functions. Vitronectin, a multi-domain protein that binds a wide variety of ligands and proteins, exists in the circulation in a preferred monomeric state, while in the extracellular matrix it exists as a multimer resulting from an altered conformation. Though the mechanism for the conformational alterations and compartmentalization in tissues is unknown, there are a number of biomolecules including PAI-1 that appear to cause such changes. Experimental analysis has established that PAI-1 induces association of vitronectin to higher-order species in a concentration-dependent fashion [1]. This report extends our investigations into the mechanism of the interaction between vitronectin and PAI-1 to explore the physiological relevance of these higher-order complexes for cellular adhesion and migration. In this study, we evaluate the effects of the pericellular microenvironment on the functions of the multimeric complexes in a variety of relevant biological settings. Our findings underscore the importance of the variability of components within this microenvironment, including different receptors and ECM components, in governing the way in which the vitronectin/PAI-1 complex mediates cell-matrix interactions.
Highlights
Vitronectin is a glycoprotein that exists in both a circulating form and a tissue-associated form in the extracellular matrix (ECM), where these respective species participate in regulating hemostasis and cell binding and migration
A role for Plasminogen activator inhibitor-1 (PAI-1) in localizing and regulating vitronectin function in the ECM. The goal of these studies was to build a representative picture of vitronectin-dependent cell adhesion and migration and how it is influenced by incorporation of PAI-1 into higher-order complexes with vitronectin and association with ECM components
These studies have used multimers promoted by PAI-1 binding that more likely replicate a physiological scenario that other forms of multimeric vitronectin generated by denaturation and renaturation have failed to achieve
Summary
Vitronectin is a glycoprotein that exists in both a circulating form and a tissue-associated form in the extracellular matrix (ECM), where these respective species participate in regulating hemostasis and cell binding and migration. While the exact mechanism for this conformational alteration, oligomerization and partitioning to different compartments in the body is unknown, vitronectin adopts specific and distinct functions in blood and the ECM Such a versatile and multifunctional role for this protein arises from its binding to a wide variety of ligands, including the thrombin-antithrombin complex [5,6], heparin [7,8,9], PAI-1 [10,11,12], complement proteins [13] and several cell surface receptors, including integrins and the urokinase plasminogen activator receptor (uPAR) [14,15,16,17,18,19,20]. Regulation of cell adhesion and migration comes from its role as a matrix protein that mediates outside-in and inside-out signaling by binding to cell surface receptors, including uPAR and certain subclasses of integrins (primarily αvβ and αvβ5) [2,14,23,24,25,26,27]
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