- Thrombospondin
Thrombospondins (TSP) are secreted proteins with
antiangiogenic abilities.Types
The thrombospondins (TSP) are a family of multifunctional proteins. The family consists of thrombospondins 1-5 and can be divided into 2 subgroups: A, which contains TSP-1 and -2, and B, which contains TSP-3, -4 and -5 (also designated cartilage oligomeric protein or COMP). TSP-1 and -2 are homotrimers, consisting of three identical subunits, whereas TSP-3, -4 and -5 are homopentamers.
TSP-1 and TSP-2 are produced by immatureastrocyte s during brain development, which promotes the development of newsynapse s. [cite journal | author = Christopherson KS, Ullian EM, Stokes CC,Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA.
title = Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. | journal = Cell | volume = 120 | issue = 3 | pages = 421–33 | year = 2005 | pmid = 15707899
doi = 10.1016/j.cell.2004.12.020]Thrombospondin 1
Thrombospondin 1 (TSP-1) is encoded by
THBS1 . It was first isolated fromplatelets that had been stimulated with thrombin, and so was designated 'thrombin-sensitive protein'. Since its first recognition, functions forTSP-1 have been found in multiple biological processes including angiogenesis, apoptosis, activation ofTGF-beta and Immune regulation. As such,TSP-1 is designated a multifunctional protein.TSP-1 has multiple receptors, among whichCD36 ,CD47 andintegrins are of particular note.TSP-1 is anantiangiogenic , inhibiting the proliferation and migration of endothelial cells by interactions with CD36 expressed on their surface of these cells. Inhibitory peptides and fragments ofTSP1 bind toCD36 , leading to the expression ofFAS ligand (FasL), which activates the expression ofFas . This leads to the activation ofcaspase s andapoptosis of the cell. Since tumors overexpressingTSP-1 typically grow slower, exhibit less angiogenesis, and have fewer metastases, TSP1 is an attractive target for cancer treatment. BecauseTSP1 is extremely large (~120 kDa monomer), not very abundant and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence fromTSP1 are being tested. One analog,ABT-510 , exhibits potent proapoptotic activity in cultured cells, while clinically it is very well tolerated with therapeutic benefits reported against several malignancies [Haviv F, Bradley MF, Kalvin DM, et al. Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. J Med Chem 2005;48:2838–46] . ABT-510 is being evaluated in phase II clinical trials for the treatment of several types of cancer [Sorbera L, Bayes M. ABT-510: oncolytic Angiogenesis Inhibitor. Drugs of the Future 2005;30:1081–6] .References
External links
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*THBS1 , Gene|THBS2, Gene|THBS3, Gene|THBS4, Gene|COMP (also known as "THBS5")
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