634 Considerable progress has been made towards understanding the function of thrombospondin-1 and -2. The description of the phenotype of mice with thrombospondin-1 and -2 knocked-out supports in vitro biochemical and cell-biological data and has opened new avenues of research. Recently, our understanding of the roles of thrombospondins in the activation of TGFβ, inhibition of angiogenesis and the initiation of signal transduction has advanced. Addresses Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, RN270C, Boston, Massachusetts 02215, USA; e-mail: lawler@mbcrr.harvard.edu Current Opinion in Cell Biology 2000, 12:634–640 0955-0674/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved. Abbreviations ADAM a disintegrin and metalloprotease domain CD47 integrin-associated protein or IAP ERK1/2 extracellular-signal-regulated protein kinase FAK focal adhesion kinase FGF-2 basic fibroblast growth factor MAPK mitogen-activated protein kinase PDGF platelet-derived growth factor PI3-K phosphatidylinositol 3-kinase TGFβ transforming growth factor β TSPs thrombospondins TSR thrombospondin type 1 repeat Introduction The thrombospondins (TSPs) are a family of extracellular proteins that participate in cell-to-cell and cell-to-matrix communication. Five family members, each representing a separate gene product, probably exist in most vertebrate species. Each of these five proteins has a specific pattern of expression in embryonic and adult tissues with most tis- sues expressing at least one family member. Many tissues, such as the heart, cartilage and brain, express most of the TSP gene products. Thrombospondin-1 was the first family member to be identified and it is a major constituent of human blood platelets. The vast majority of structural and functional studies have been performed with TSP-1 because it is readily purified from human blood platelets. From these studies and from the results of ‘knock-out’ experiments, a model for the functions of the TSPs is emerging. The TSPs appear to function at the cell surface to bring together membrane proteins and cytokines that regulate extracel- lular matrix structure and cellular phenotype. The membrane proteins that participate in these complexes include integrins, the integrin-associated protein (also known as CD47 or IAP), CD36 and proteoglycans. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) also bind to TSP-1. Thus, it appears that the function of TSP-1 is to direct the formation of multiprotein complexes that modulate cellular phenotype in much the same way that the formation of multiprotein complexes regulate cell adhesion, signal transduction and transcription. As each cell expresses a different repertoire of receptors, the composition of the complexes and the cellular responses varies with the cell type. For example, TSP-1 stimulates or inhibits the migration of vascular smooth muscle cells or endothelial cells, respectively. Like most large extracellular proteins, the TSPs are com- posed of several structural domains that reflect exon shuffling during evolution. Each subunit of TSP-1 consists of amino- and carboxy-terminal globular domains, a region of homology with procollagen, and three types of repeated sequence motifs designated type 1, type 2 and type 3 repeats (Figure 1). Molecular cloning of TSP-2, -3, -4 and -5 (TSP-5 is also known as cartilage oligomeric matrix protein or COMP) indicates that the thrombospondin gene family can be divided into two subgroups on the basis of their molecular architecture. TSP-1 and -2 (subgroup A) have the same set of structural domains. The subgroup A TSPs are members of the thrombospondin type-1 repeat (TSR) supergene family, which includes proteins that con- tain varying numbers of TSRs. These structural motifs are found in complement factors, proteins involved in axon guidance, members of the ADAM (a disintegrin and met- alloprotease domain) family and proteins involved in the regulation of angiogenesis. The properties of the TSR family members that are involved in axon guidance have recently been reviewed [1]. In this review, the role of the TSRs in the activation of TGFβ and the inhibition of angiogenesis is discussed. Considerable progress has been made towards an under- standing of the function of TSP-1 and -2. In particular, the role of TSP-1 in the activation of TGFβ and the role of TSP-1 and -2 in angiogenesis and tumor growth have been elucidated. In addition, TSP-2 has been shown to be important for assembly of collagen fibrils in the skin [2]. At a cellular level, a site for α3β1-integrin binding and some of the signaling events that are initiated by TSP-1 have been identified [3 • ]. Furthermore, the interaction of sig- naling pathways downstream of the various TSP-1 receptors has been described. These recent discoveries will be the focus of this review. Activation of TGFβ by TSP-1 In 1992, Murphy-Ullrich and coworkers [4] reported that TSP-1 binds and activates TGFβ. Since that initial obser- vation, fusion proteins and synthetic peptides have been used to explore the molecular basis of this interaction, and TSP-1 null mice have been used to show that TSP-1 acti- vates TGFβ in epithelial tissues (for a review see [5]). The functions of thrombospondin-1 and -2 Jack Lawler