Thrombospondin as a mediator of cancer cell adhesion in metastasis.
Thrombospondin (TSP) is a 450 kDa adhesive glycoprotein. It is present in high concentrations in the platelet alpha-granule and can readily be secreted following platelet activation where local concentrations can be increased by 3-4 orders of magnitude. TSP is also synthesized by a variety of other cells and is incorporated into their extracellular matrix. TSP is a homotrimer with a number of functional domains, at least four of which might serve as receptor recognizing regions. The amino-terminal heparin binding domain interacts with heparin, other glycosaminoglycans and glycolipids and likely recognizes specific cell surface proteoglycans. The central disulfide cross-linked region, 210 kDa non-reduced and 70 kDa reduced, contains a peptide motif CSVTCG which is apparently responsible for binding to glycoprotein IV (CD36) with high affinity. Immediately adjacent to the calcium binding region of TSP, which undergoes considerable molecular relaxation in the absence of calcium, is an RGDA sequence. TSP has been demonstrated to bind to integrins of the alpha v beta 3 and alpha IIb beta 3 class. The carboxy-terminal region of TSP also contains at least one binding epitope for a cell receptor. There are 2 well characterized genes for TSP and truncated forms of TSP have been detected which have inhibitory effects on angiogenesis. Finally, TSP can interact with fibrinogen and fibronectin, perhaps on cellular surfaces, which might serve as secondary receptor-like mechanisms for TSP binding and subsequent mediation of cell adhesion.
Walz
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Wayne State University School of Medicine, Department of Physiology, Detroit, MI 48201.
D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D018955:CD36 Antigens; D002352:Carrier Proteins / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D016024:Receptors, Cytoadhesin / Q000502:physiology; D019699:Thrombospondins
D018955:CD36 Antigens; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D010980:Platelet Membrane Glycoproteins; D016024:Receptors, Cytoadhesin; D019699:Thrombospondins