Angiostatin

Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor (i.e., it blocks the growth of new blood vessels), and it is currently undergoing clinical trials for its use in anticancer therapy.[1]

Structure

Angiostatin is a 38 kDa fragment of a larger protein, plasmin (itself a fragment of plasminogen) enclosing three to five contiguous kringle modules. Each module contains two small beta sheets and three disulfide bonds.[2][3]

Generation

Angiostatin is produced, for example, by autoproteolytic cleavage of plasminogen, involving extracellular disulfide bond reduction by phosphoglycerate kinase. Furthermore, angiostatin can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostate-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.

Biological activity

Angiostatin is known to bind many proteins, especially to angiomotin and endothelial cell surface ATP synthase but also integrins, annexin II, C-met receptor, NG2 proteoglycan, tissue-type plasminogen activator, chondroitin sulfate proteoglycans, and CD26. Additionally, smaller fragments of angiostatin may bind several other proteins. There is still considerable uncertainty on its mechanism of action, but it seems to involve inhibition of endothelial cell migration,[4] proliferation and induction of apoptosis. It has been proposed that angiostatin activity is related, among other things, to the coupling of its mechanical and redox properties.[5]

References

  1. ↑ Safety and Efficacy Study of rhAngiostatin Administered in Combination With Paclitaxel and Carboplatin to Patients With Non-Small-Cell Lung Cancer - Full Text View - ClinicalTrials.gov
  2. ↑ Cao Y, Ji RW, Davidson D, et al. (November 1996). "Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells". The Journal of Biological Chemistry. 271 (46): 29461–7. doi:10.1074/jbc.271.46.29461. PMID 8910613. Retrieved 2009-06-18.
  3. ↑ O'Reilly MS, Holmgren L, Shing Y, et al. (October 1994). "Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma". Cell. 79 (2): 315–28. doi:10.1016/0092-8674(94)90200-3. PMID 7525077.
  4. ↑ Redlitz A, Daum G, Sage EH (1999). "Angiostatin diminishes activation of the mitogen-activated protein kinases ERK-1 and ERK-2 in human dermal microvascular endothelial cells". Journal of Vascular Research. 36 (1): 28–34. doi:10.1159/000025623. PMID 10050071.
  5. ↑ Grandi F, Sandal M, Guarguaglini G, Capriotti E, Casadio R, Samorì B (November 2006). "Hierarchical mechanochemical switches in angiostatin". Chembiochem : a European Journal of Chemical Biology. 7 (11): 1774–82. doi:10.1002/cbic.200600227. PMID 16991168.

External links


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