The thrombospondins

School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom.
Cold Spring Harbor perspectives in biology (Impact Factor: 8.23). 08/2011; 3(10):a009712. DOI: 10.1101/cshperspect.a009712
Source: PubMed

ABSTRACT Thrombospondins are evolutionarily conserved, calcium-binding glycoproteins that undergo transient or longer-term interactions with other extracellular matrix components. They share properties with other matrix molecules, cytokines, adaptor proteins, and chaperones, modulate the organization of collagen fibrils, and bind and localize an array of growth factors or proteases. At cell surfaces, interactions with an array of receptors activate cell-dependent signaling and phenotypic outcomes. Through these dynamic, pleiotropic, and context-dependent pathways, mammalian thrombospondins contribute to wound healing and angiogenesis, vessel wall biology, connective tissue organization, and synaptogenesis. We overview the domain organization and structure of thrombospondins, key features of their evolution, and their cell biology. We discuss their roles in vivo, associations with human disease, and ongoing translational applications. In many respects, we are only beginning to appreciate the important roles of these proteins in physiology and pathology.

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Available from: Josephine C Adams, Jul 14, 2015
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    • "To determine whether or not TSPs affect STIM1 function, we overexpressed COMP in HEK 293 cells, which express endogenous STIM1, but not endogenous TSPs. We chose COMP for these studies because it lacks the N-terminal domain and the type 1 repeats that are found in other TSPs and have been shown to mediate numerous cellular functions (Adams and Lawler, 2011). Interestingly, stable over-expression of COMP in HEK 293 cells resulted in a variable (25 ± 15%, n = 8, p = 0.0038) increase in total STIM1 expression (Fig. 2D). "
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    ABSTRACT: The thrombospondins (TSPs) are a family of matricellular proteins that regulate cellular phenotype through interactions with a myriad of other proteins and proteoglycans. We have identified a novel interaction of the members of the TSP gene family with stromal interaction molecule 1 (STIM1). This association is robust since it is preserved in Triton X-100, can be detected with multiple anti-TSP-1 and anti-STIM1 antibodies, and is detected in a wide range of cell types. We have also found that STIM1 co-immunoprecipitates with TSP-4 and cartilage oligomeric matrix protein (COMP), and that a recombinant version of the N-terminal domain of STIM1 binds to the signature domain of TSP-1 and COMP. The association of the TSPs with STIM1 is observed in both the presence and absence of calcium indicating that the calcium-dependent conformation of the signature domain of TSPs is not required for binding. Thus, this interaction could occur in the ER under conditions of normal or low calcium concentration. Furthermore, we observed that the expression of COMP in HEK 293 cells decreases STIM1-mediated calcium release activated calcium (CRAC) channel currents and increases arachidonic acid calcium (ARC) channel currents. These data indicate that the TSPs regulate STIM1 function and participate in the reciprocal regulation of two channels that mediate calcium entry into the cell.
    Matrix Biology 07/2014; 37. DOI:10.1016/j.matbio.2014.05.004 · 3.65 Impact Factor
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    • "Proteomic analysis and expression studies suggest that additional matricellular proteins might contribute to heart development. One such protein is Thrombospondin (Tsp); the Drosophila genome contains a single tsp gene, which is most closely homologous to mammalian Tsp4 and Tsp3 (Adams and Lawler, 2011). In embryos, the most prominent cells expressing Tsp are tendon cells, and Tsp had been shown to regulate the correct formation of the myo-tendinous junction by directing proper distribution of ECM components into this site. "
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    ABSTRACT: The Drosophila model represents an attractive system in which to study the functional contribution of specific genes to organ development. Within the embryo, the heart tube serves as an informative developmental paradigm to analyze functional aspects of matricellular proteins. Here, we describe two essential extracellular matricellular proteins, Multiplexin (Mp) and Lonely heart (Loh). Each of these proteins contributes to the development and morphogenesis of the heart tube by regulating the activity/localization of essential extracellular proteins. Mp, which is secreted by heart cardioblasts and is specifically distributed in the lumen of the heart tube, binds to the signaling protein Slit, and facilitates its local signaling at the heart's luminal domain. Loh is an ADAMTS-like protein, which serves as an adapter protein to Pericardin (a collagen-like protein), promoting its specific localization at the abluminal domain of the heart tube. We also introduce the Drosophila orthologues of matricellular proteins present in mammals, including Thrombospondin, and SPARC, and discuss a possible role for Teneurins (Ten-A and Ten-M) in the heart. Understanding the role of these proteins provides a novel developmental perspective into the functional contribution of matricellular proteins to organ development.
    Matrix biology: journal of the International Society for Matrix Biology 04/2014; 37. DOI:10.1016/j.matbio.2014.03.006 · 3.65 Impact Factor
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    • "The different TSPs are expressed throughout the organism at various stages of mammalian development [98]. In the CNS, TSPs 1 and 2 are expressed in cultured and developing astrocytes, with expression peaking during the first postnatal week in mice [102] [103]. "
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    ABSTRACT: Matricellular proteins are secreted, nonstructural proteins that regulate the extracellular matrix (ECM) and interactions between cells through modulation of growth factor signaling, cell adhesion, migration, and proliferation. Despite being well described in the context of nonneuronal tissues, recent studies have revealed that these molecules may also play instrumental roles in central nervous system (CNS) development and diseases. In this minireview, we discuss the matricellular protein families SPARC (secreted protein acidic and rich in cysteine), Hevin/SC1 (SPARC-like 1), TN-C (Tenascin C), TSP (Thrombospondin), and CCN (CYR61/CTGF/NOV), which are secreted by astrocytes during development. These proteins exhibit a reduced expression in adult CNS but are upregulated in reactive astrocytes following injury or disease, where they are well placed to modulate the repair processes such as tissue remodeling, axon regeneration, glial scar formation, angiogenesis, and rewiring of neural circuitry. Conversely, their reexpression in reactive astrocytes may also lead to detrimental effects and promote the progression of neurodegenerative diseases.
    Neural Plasticity 01/2014; 2014:321209. DOI:10.1155/2014/321209 · 3.60 Impact Factor
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