é 5 Regulation of Cell Behavior by Extracellular Proteins Amy D. Bradshaw Dept. of Medicine, Medical University of South Carolina, Charleston and the Ralph H. Johnson Department of Veteran's Affair Medical Center, Charleston, South Carolina INTRODUCTION ‘The extracellular miliew is critical for the control of the behavior of every cell in all tissues. Many factors can contribute to the environment of a cell, for example, cell-cell contact, growth factors, extracellular matrix (ECM) proteins, and matricellular proteins. All of these components act together to regulate cell surface protein activity, intracellular signal ‘transduction, and subsequent gene expression which leads to proliferation, migration, differentiation, and ultimately the formation of complex tissues. This chapter will focus on matricellular proteins as modulators of extracellular signals. The matricellular proteins are characterized as secreted, modular proteins that are associated with the extracellular matrix but do not act as structural constituents [1]. Presumably, the function of matricellular proteins is to provide a link between the extracellular matrix and cell surface receptors, or cytokines and proteases localized in the extracellular environment whose activity might be affected by this interaction [1]. Thrombospondin 1 and 2, tenascin-C, osteopontin, and SPARC are representatives of this class of proteins. A growing body of evidence points to these proteins as important mediators of growth factor, ECM, and cell signaling pathways (able 15.1). Consequently, in vitro systems designed to mimic tissue conditions should consider the influence of matricellular proteins. THROMBOSPONDIN-1 ‘Thrombospondin-1 is a 450,000 dalton glycoprotein with seven modular domains [2]. To date, five different paralogs of thrombspondin have been identified, termed thrombosponi 1-5. This chapter will review the two more characterized forms, thrombospondin-1 and. thrombospondin-2. At least five different ECM-associated proteins are able to bind to thrombospondin-1: collagens | and V, fibronectin, laminin, fibrinogen and SPARC [2]. Likewise, cell surface receptors for thrombospondin are numerous, and include the integrin family of extracellular matrix receptors [3]. Given the significant number and variety of thromboypondin-I-binding proteins, it is of little surprise that a wide variety of functions have been attributed to this protein, some of which appear to be contradictory. Many of these ies may, however, actually reflect the dynamic interaction of thrombespondin-1 with Lpiinalenigmumnonmmonans oft Payee char) een ede Beh CHAPTER 279