Thrombospondins as matricellular modulators of cell function

Matricellular proteinsThrombospondins (TSPs) are a small family of secreted, modular glycoproteins whose functions, at a mechanistic level, are not well understood, despite increasing scrutiny in recent years.TSP1 and TSP2 form one subgroup and are trimers with a chain molecular mass of about 145 kDa.The pentameric TSPs 3-5 are significantly smaller, with a subunit molecular mass of about 100 kDa (1), and their physiological roles are probably distinct.This Perspective will concern itself with TSP1 and TSP2. TSP1 and TSP2 as matricellular proteinsUnlike the various structural proteins of the ECM, TSP1 and TSP2 do not appear to contribute directly to the integrity of a physical entity, such as a fiber or a basement membrane.Rather, it seems that these proteins act contextually to influence cell function by modulating cell-matrix interactions.TSP1 and TSP2 can interact with specific cell-surface receptors, cytokines, growth factors, and proteases, and the availability of each of these diverse molecules may help define their function in a given environment.These properties are shared by other nonhomologous but functionally similar proteins such as SPARC, tenascin C, and osteopontin, some of which are the subject of other Perspectives in this series, and have led to the application of the term "matricellular" to this group of proteins (2).Because no orthologues of TSP1 and TSP2 can be found in the genomes of Caenorhabditis elegans or Drosophila (3), it appears that these two proteins do not play fundamental roles in metazoan biology but have evolved to deal with the increased complexity of cellmatrix interactions in vertebrates.Matricellular proteins share a number of other characteristics.These proteins are expressed primarily during development, during growth, and in response to injury, and they are not abundant in the normal adult animal, except in tissues with continued turnover, such as bone.Furthermore, targeted disruption of the murine genes encoding these proteins produces an apparently normal or subtle phenotype, although more careful scrutiny and appropriate challenges have revealed clear-cut and often unanticipated abnormalities (refs.4-6; and see other Perspectives in this series).These findings are in contrast to the phenotypes of mice Thrombospondins as matricellular modulators of cell function