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Gene Review

THBS1  -  thrombospondin 1

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Disease relevance of THBS


High impact information on THBS

  • Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism [6].
  • The RGD sequence is located in the type 3 repeat region of TSP that has multiple Ca2+ binding sites and is subject to a complex intramolecular thiol-disulfide isomerization [7].
  • Thrombospondin (TSP) contains the Arg-Gly-Asp (RGD) sequence that is thought to be important for cell adhesion mediated by several cell-surface integrin receptors [7].
  • Lower DTT concentrations were required for enhancement of the adhesive activity of TSP if Ca2+ was chelated with EDTA [7].
  • Disulfides modulate RGD-inhibitable cell adhesive activity of thrombospondin [7].

Chemical compound and disease context of THBS

  • The effects of hypoxia both on the stabilization of the TSP-1 transcript and the stimulation of TSP-1 protein production are completely inhibited by arginine butyrate [5].
  • The TSP-1 induction by hypoxia is a graded and reversible physiologic response and can be mimicked by the use of cobalt chloride or the inhibition of nitric oxide production, suggesting both the involvement of a heme-containing oxygen sensor and a role for the endogenous production of nitric oxide in TSP-1 regulation [5].

Biological context of THBS


Anatomical context of THBS


Associations of THBS with chemical compounds

  • Using a microchemotaxis chamber, VSMCs pre-incubated in SFM, DMSO (vehicle control), PD98059 (10 microM), or SB202190 (10 microM) were exposed to each domain, TSP-1, or SFM [1].
  • The structure and the mechanical properties of fibrin clots are influenced by various macromolecules (i.e., hyaluronic acid and thrombospondin) and also by pH, ionic strength, and thrombin concentrations of the milieu in which they polymerize [12].
  • Thrombospondin, a high molecular weight glycoprotein secreted by platelets in response to activation by thrombin, has been identified by immunofluorescence in bovine aortic endothelial cells, human foreskin fibroblasts, and human aortic smooth muscle cells [13].
  • The inhibition of chemotaxis and spreading by antibodies against the beta 3 but not the beta 1 chain of the integrin receptor points to a role for the integrins in the interaction of endothelial cells with TSP [14].
  • The interaction of the heparin-binding domain of TSP with cell-associated heparan sulfate appears to be an important mechanistic component for this activity of TSP [15].

Physical interactions of THBS

  • A binding assay was used to determine the specificity of TSP-1 binding to MMP2 [4].
  • We have previously shown that both heparin and fibronectin have two binding sites on the TSP-1 subunit which may require conformational change for their occupancy (R. Dardik and J. Lahav, 1987, Eur. J. Biochem. 168, 347; ibid 1989, 185, 581) [16].

Regulatory relationships of THBS

  • CONCLUSION: TSP-1 induced MMP2 activation through transcriptional and posttranslational mechanisms [4].
  • In addition, we correlated this biphasic effect on tube formation with the capacity of TSP-1 to stimulate the activity of a matrix metalloproteinase-9 (MMP-9) in BAE cell collagen gel cultures [17].

Other interactions of THBS


Analytical, diagnostic and therapeutic context of THBS


  1. Thrombospondin-1-induced vascular smooth muscle cell chemotaxis: the role of the type 3 repeat and carboxyl terminal domains. Lee, T., Nesselroth, S.M., Olson, E.T., Esemuede, N., Lawler, J., Sumpio, B.E., Gahtan, V. J. Cell. Biochem. (2003) [Pubmed]
  2. Thrombospondin expression in aldosterone-producing adenomas. Hatakeyama, H., Nishizawa, M., Nakagawa, A., Nakano, S., Kigoshi, T., Miyamori, I., Uchida, K. Hypertens. Res. (2002) [Pubmed]
  3. Effects of thrombospondin antibody on the recovery of endothelial cells from hyperthermia. Ketis, N.V., Lawler, J. J. Cell. Sci. (1990) [Pubmed]
  4. Thrombospondin-1 induces matrix metalloproteinase-2 activation in vascular smooth muscle cells. Lee, T., Esemuede, N., Sumpio, B.E., Gahtan, V. J. Vasc. Surg. (2003) [Pubmed]
  5. Hypoxia increases thrombospondin-1 transcript and protein in cultured endothelial cells. Phelan, M.W., Forman, L.W., Perrine, S.P., Faller, D.V. J. Lab. Clin. Med. (1998) [Pubmed]
  6. Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. Schultz-Cherry, S., Murphy-Ullrich, J.E. J. Cell Biol. (1993) [Pubmed]
  7. Disulfides modulate RGD-inhibitable cell adhesive activity of thrombospondin. Sun, X., Skorstengaard, K., Mosher, D.F. J. Cell Biol. (1992) [Pubmed]
  8. Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development. Greenaway, J., Gentry, P.A., Feige, J.J., LaMarre, J., Petrik, J.J. Biol. Reprod. (2005) [Pubmed]
  9. The molecular structure of corticotropin-induced secreted protein, a novel member of the thrombospondin family. Pellerin, S., Lafeuillade, B., Wade, R.H., Savona, C., Chambaz, E.M., Feige, J.J. J. Biol. Chem. (1993) [Pubmed]
  10. Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration. Orr, A.W., Elzie, C.A., Kucik, D.F., Murphy-Ullrich, J.E. J. Cell. Sci. (2003) [Pubmed]
  11. Opposite regulation of thrombospondin-1 and corticotropin-induced secreted protein/thrombospondin-2 expression by adrenocorticotropic hormone in adrenocortical cells. Lafeuillade, B., Pellerin, S., Keramidas, M., Danik, M., Chambaz, E.M., Feige, J.J. J. Cell. Physiol. (1996) [Pubmed]
  12. The configuration of fibrin clots determines capillary morphogenesis and endothelial cell migration. Nehls, V., Herrmann, R. Microvasc. Res. (1996) [Pubmed]
  13. Thrombospondin: synthesis and secretion by cells in culture. Raugi, G.J., Mumby, S.M., Abbott-Brown, D., Bornstein, P. J. Cell Biol. (1982) [Pubmed]
  14. Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: a potential angiogenesis regulatory factor. Taraboletti, G., Roberts, D., Liotta, L.A., Giavazzi, R. J. Cell Biol. (1990) [Pubmed]
  15. Thrombospondin modulates focal adhesions in endothelial cells. Murphy-Ullrich, J.E., Höök, M. J. Cell Biol. (1989) [Pubmed]
  16. Functional changes in the conformation of thrombospondin-1 during complexation with fibronectin or heparin. Dardik, R., Lahav, J. Exp. Cell Res. (1999) [Pubmed]
  17. Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells. Qian, X., Wang, T.N., Rothman, V.L., Nicosia, R.F., Tuszynski, G.P. Exp. Cell Res. (1997) [Pubmed]
  18. Thrombospondins selectively activate one of the two latent forms of transforming growth factor-beta present in adrenocortical cell-conditioned medium. Souchelnitskiy, S., Chambaz, E.M., Feige, J.J. Endocrinology (1995) [Pubmed]
  19. Effects of heat shock on the expression of thrombospondin by endothelial cells in culture. Ketis, N.V., Lawler, J., Hoover, R.L., Karnovsky, M.J. J. Cell Biol. (1988) [Pubmed]
  20. Thrombospondin binding to specific sequences within the A alpha- and B beta-chains of fibrinogen. Bacon-Baguley, T., Ogilvie, M.L., Gartner, T.K., Walz, D.A. J. Biol. Chem. (1990) [Pubmed]
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