The structure of human platelet thrombospondin.

191

Platelet adhesion to the subendothelial matrix and the subsequent aggregation of the activated platelets is a special case of intercellular adhesion that is highly regulated and for which multiple, possibly redundant adhesive systems exist. The large "adhesive glycoproteins" such as fibrinogen, von Willebrand factor, and fibronectin and their receptors, which participate in platelet adhesion and aggregation, are not unique to platelets, and probably serve analogous functions in a variety of cell types and locations. Thrombospondin (TS)/the most abundant protein of platelet alpha-granules, has been recognized as a new member of this class of adhesive glycoproteins. Whereas other adhesive glycoproteins are contained within alpha-granules and secreted upon platelet activation, they also exist in plasma at high concentrations. Hence TS is the only member of the group that is unique to alpha-granules and whose expression in quantity at sites of platelet aggregation is absolutely dependent on platelet activation.Since its discovery in 1971, TS has been thought to have a role in platelet aggregation (3,4). This suspicion has recently been confirmed by the fnding that both monoclonal (14) and polyclonal (22, 37) antibodies against platelet TS can block the secondary or secretion-dependent phase of platelet aggregation. This result in itself, however, does not speak directly to the mechanism of TS involvement in this complex process, since antibodies against fibrinogen (62), fibronectin (13), and the platelet glycoprotein IIb/IIIa (43), the receptor on platelets for fibrinogen and fibronectin, will all block platelet aggregation. Other agents that block aggregation are short peptide sequences related either to RGDS, the cellbinding sequence of fibronectin and fibrinogen (21), or to the COOH-terminal segment of the fibrinogen gamma chain (27). Both interfere with the binding of fibrinogen, fibronectin (58), and presumably yon Willebrand factor (61) to IIb/IIIa.In addition to its localization in platelets and its presumed synthesis in megakaryocytes (42), TS has been found, using immunofluorescence localization techniques, in a variety of extracellular locations in human tissues including blood vessel, muscle, skin, kidney, and glandular epithelium (64). The biosynthesis of TS has been demonstrated in a number of normal and transformed cells in culture, including endothelial, smooth muscle, and glial cells, type II pneumocytes, fibroblasts, keratinocytes, and macrophages (1,25,26,45,46,50,57,65). Furthermore, several cell lines derived from malignancies such as HT-1080 fibrosarcoma cells and the melanoma lines C32 and G361 also make TS (54,63). This widespread expression of TS and its appearance as a component of the extracellular matrix have led to the suggestion that TS might have a role analogous to that of fibronectin and laminin in cell attachment, motility, and perhaps differentiation. TS does not appear to be an obligatory attachment factor for cultured cells such as fibroblasts, smooth muscle cells, or endothelial ...

Section: Modular Structure Of Thrombospondinmentioning

confidence: 99%

Section: Modular Structure Of Thrombospondinmentioning

confidence: 99%

Thrombospondin: a modular adhesive glycoprotein of platelets and nucleated cells.

Frazier¹

1987

191

“…p LATELET thrombospondin is a 420,000-D glycoprotein that is structurally and functionally similar to the adhesive glycoproteins (Lawler and Hynes, 1986). Multiple structural domains can be discerned on an electron microscopic level (Galvin et al, 1985;Lawler et al, 1985). Globular domains at the NH2 and COOHterminals are involved in the interaction of thrombospond'm with the cell surface (Gartner et al, 1984;Dixit et al, 1985;Clezardin et al, 1988;Sun et al, 1989;Kosfeld et al, 1991).…”

mentioning

confidence: 99%

Identification and characterization of thrombospondin-4, a new member of the thrombospondin gene family.

Lawler

Duquette

Whittaker

et al. 1993

Self Cite

132

A new member of the thrombospondin gene family, designated thrombospondin-4, has been identified in the Xenopus laevis genome. The predicted amino acid sequence indicates that the protein is similar to the other members of this gene family in the structure of the type 3 repeats and the COOH-terminal domain. Thrombospondin-4 contains four type 2 repeats and lacks the type 1 repeats that are found in thrombospondin-1 and 2. The amino-terminal domain of thrombospondin-4 has no significant homology with the other members of the thrombospondin gene family or with other proteins in the database. RNAse protection analysis establishes that the initial expression of Xenopus thrombospondin-4 is observed during neurulation. Levels of mRNA expression increase twofold during tailbud stages but decrease by the feeding tadpole stage. The size of the thrombospondin-4 message is 3.3 Kb and 3.4 Kb in the frog and human, respectively. Northern blot analysis of human tissues reveals high levels of thrombospondin-4 expression in heart and skeletal muscle, low levels in brain, lung and pancreas and undetectable levels in the placenta, liver and kidney. These data establish the existence of a new member of the thrombospondin gene family that may participate in the genesis and function of cardiac and skeletal muscle.

“…Thrombospondin (TSP) is a trimeric adhesive glycoprotein present in the extracellular matrix and on the surface of many cell types. Like other ECM components, it binds a number of ligands including fibronectin (Lahav et al, 1982(Lahav et al, , 1984, collagens (Lahav et al, 1982;Mumby et al, 1984), glycosaminoglycans (Dixit et al, 1984;Lawler et al, 1985), as well as plasminogen and plasminogen activators (Silverstein et al, 1984). TSP may play an important role in mor-phogenesis by both determining the organization of the matrix via its binding of other ECM components and by directing local protease activity via its binding of plasminogen activators (Silverstein and Nachman, 1987).…”

mentioning

confidence: 99%

Role of the extracellular matrix protein thrombospondin in the early development of the mouse embryo.

O’Shea

Liu

Kinnunen

et al. 1990

Abstract. The distribution of the extracellular matrix protein thrombospondin (TSP) in cleavage to egg cylinder staged mouse embryos and its role in trophoblast outgrowth from cultured blastocysts were examined. TSP was present within the cytoplasm of unfertilized eggs; in fertilized one-to four-cell embryos; by the eight-cell stage, TSP was also densely deposited at cell-cell borders. In the blastocyst, although TSP was present in all three cell types; trophectoderm, endoderm, and inner cell mass (ICM), it was enriched in the ICM and at the surface of trophectoderm cells. Hatched blastocysts grown on matrix-coated coverslips formed extensive trophoblast outgrowths on TSP, grew slightly less avidly on laminin, or on a 140-kD fragment of TSP containing its COOH terminus and putative cell binding domains. There was little outgrowth on the NH2 terminus heparin-binding domain. Addition of anti-TSP antibodies (but not GRGDS) to blastocysts growing on TSP strikingly inhibited outgrowth. Consistent with its early appearance and presence in trophoblast cells during implantation, TSP may play an important role in the early events involved in mammalian embryogenesis.