The thrombospondins

Abstract

Thrombospondin-1 (TSP-1) was studied in the 1980s as a major component of platelet alpha-granules released upon platelet activation and also as a cell adhesion molecule. In 1993, we published a short review that discussed the exciting identification by molecular cloning of four additional vertebrate gene products related to TSP-1 [Current Biology 3 (1993) 188]. We put forward a structurally based classification for the newly identified proteins and discussed the functional and evolutionary implications of the new gene family. Since that time, the depth and breadth of knowledge on vertebrate TSPs and their functions in cells and tissues in health and disease has expanded into important new areas. Of particular interest is the new knowledge on the complex, domain and cell-type specific effects of TSPs on cell-signaling and cell-adhesion behaviour, the roles of TSP-1 and TSP-2 as anti-angiogenic agents, the roles of TSP-1 and TSP-2 in wound-healing, and associations of point mutations and polymorphisms in TSP-1, TSP-4 and TSP-5/COMP with human genetic diseases. The TSP family also now includes invertebrate members. In this article, we give the 2004 view on TSPs and our perspectives on the significant challenges that remain. Other articles in this issue discuss the functions of vertebrate TSPs in depth.

Fig. 1

Functions of TSPs. Key: experimentally demonstrated function (+), or absence of activity (−). For proliferation, S: stimulation, I: inhibition and depends on the cell-type. NT: not tested. Underlined properties are known to be mediated by the type 1 repeats and are therefore unlikely to be shared in pentameric TSPs by the same mechanism. (*): indicates function is cell-type dependent, either because of cell-binding to different TSP domains or because of the interaction of different cell-type-specific receptors with the same TSP domain. Cell-cell interactions include binding of parasitised red blood cells to endothelium, binding of T cells to activated endothelium, macrophage interactions with apoptotic cells, and neurite outgrowth on appropriate cell layers.

Fig. 2

Domain architecture of TSPs. The diagram shows the domain composition of the various forms of TSPs. Red box indicates the cassette of domains that is conserved in all TSPs. Major distinct domain functions are listed underneath subgroup A and suggest several possibilities for clinical translation (see text).