Advances in Biological Chemistry, 2013, 3, 114-132 ABC http://dx.doi.org/10.4236/abc.2013.31015 Published Online February 2013 (http://www.scirp.org/journal/abc/ ) The cellular microenvironment modulates the role of PAI-1 and vitronectin in mediating cell-matrix interactions Sumit Goswami, Lawrence C. Thompson, Lindsay Wickman, Cynthia B. Peterson The Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, USA Email: cbpeters@utk.edu Received 25 October 2012; revised 26 November 2012; accepted 2 December 2012 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, re- cent emphasis has also focused on its protease-inde- pendent functions. Vitronectin, a multi-domain pro- tein 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 alte- rations and compartmentalization in tissues is un- known, there are a number of biomolecules including PAI-1 that appear to cause such changes. Experi- mental analysis has established that PAI-1 induces association of vitronectin to higher-order species in a concentration-dependent fashion [1]. This report ex- tends 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 mi- croenvironment on the functions of the multimeric complexes in a variety of relevant biological settings. Our findings underscore the importance of the vari- ability 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. Keywords: PAI-1; Vitronectin; Extracellular Matrix; Receptors 1. INTRODUCTION Vitronectin is a glycoprotein that exists in both a cir- culating form and a tissue-associated form in the ex- tracellular matrix (ECM), where these respective species participate in regulating hemostasis and cell binding and migration. In blood, vitronectin exists primarily in a mo- nomeric form, whereas in the ECM it exists as a higher- order multimer [2-4]. While the exact mechanism for this conformational alteration, oligomerization and partition- ing 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 [7-9], PAI-1 [10-12], complement proteins [13] and several cell surface receptors, including in- tegrins and the urokinase plasminogen activator receptor (uPAR) [14-20]. Through these various interactions, vi- tronectin regulates many physiological and pathological processes in the realm of fibrinolysis, thrombosis, coagu- lation, wound healing, and cell adhesion and/or migra- tion [21-23]. 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 αvβ3 and αvβ5) [2,14,23-27]. PAI-1 is a binding partner for vitronectin and is a member of the serpin (ser ine p rotease in hibitor) family of proteins, acting as the primary inhibitor of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) [28]. Like vitronectin, PAI-1 is found in both the circulation and the ECM, where it regulates the formation of plasmin and contributes to the control of thrombolysis and pericellular proteolysis [29,30]. Such protease-dependent effects of PAI-1 have been recog- nized for a long while, although more recent work has highlighted ways in which PAI-1 functions in a protease- independent fashion. For example, a noteworthy prote- ase-independent function of PAI-1 is the regulation of cell surface receptor interactions with ECM-associated vitronectin. PAI-I has been shown to physically interfere with the interaction of uPAR and integrin receptors with vitronectin, blocking uPAR mediated binding of vitro- OPEN ACCESS