Diversity of Function Is Inherent in Matricellular Proteins: an Appraisal of Thrombospondin I

R current appreciation of the involvement of hrombospondin 1 (TSP1) 1 in diverse biological processes (Fig. 1; 1, 3, 25) extends far beyond the role initially attributed to the protein in platelet aggregation and coagulation. This diversity of function has led to considerable confusion in the literature and skepticism among scientists that a single protein can subserve such protean, sometimes conflicting, functions. In this Commentary I will attempt to show that the ability of matricellular proteins, as defined below, to interact with a wide range of both matrix proteins and cell surface receptors can explain the complex biological functions of TSP1 and resolve many of the controversies regarding its mode of action. A conclusion of this analysis is that, even if allowances are made for some errors in experimentation and interpretation, the majority of the reported functions of TSP1, divergent as they appear to be, are likely to be correct. The term "matricellular" is used in this analysis to refer to a group of modular, extracellular proteins whose functions are achieved by binding to matrix proteins as well as to cell surface receptors, or to other molecules such as cytokines and proteases that interact, in turn, with the cell surface. In addition to TSP1, this group is likely to include members of the tenascin protein family, SPARC/osteonectin and its relatives, and osteopontin. Although matricellular proteins can be associated with structural elements such as collagen fibrils or basement membranes, it is presumed that they do not contribute to the structural integrity of these elements. An association could, nevertheless, serve to sequester matricellular proteins, and provide a source of the proteins for subsequent recruitment to the cell surface. It should be noted that the distinction between structural matrix and matricellular proteins is not complete, since proteins such as fibronectin and laminin, which do serve as integral components of structural elements, also have adhesive functions and play biological roles that partially overlap those of matricellular proteins. Furthermore, matricellular proteins may participate in the formation of structural complexes under some circum-