Angiostatin

Jump to: navigation, search

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, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.

Biological activity

Angiostatin is known to bind a lot of proteins, especially to angiomotin and endothelial cell surface ATP synthase but also integrins, annexin II, C-met receptor, NG2-proteoglycans, tissue-type plasminogen activator, chondroitin sulfate proteoglycans, and CD26. Also smaller fragments of angiostatin has been shown to bind several other proteins. There is still considerable uncertainty on its mechanism of action, but it seems to involve for example 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. http://www.clinicaltrials.gov/ct/gui/show/NCT00049790;jsessionid=91EE48B7C2F7D935B96F12E31D5609E3?order=1.
  2. Kringle Domains of Human Angiostatin; Journal of Biological Chemistry, Volume 271, Number 46, Issue of November 15, 1996 pp. 29461-29467
  3. Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma; Cell, Vol 79, 315-328, 21 October 1994
  4. Alexander Redlitz, Guenter Daum, E.Helene Sage; Angiostatin Diminishes Activation of the Mitogen-Activated Protein Kinases ERK-1 and ERK-2 in Human Dermal Microvascular Endothelial Cells; Journal of Vascular Research 1999;36:28-34 (DOI: 10.1159/000025623)
  5. Fabio Grandi, Massimo Sandal, Giovanni Guarguaglini, Emidio Capriotti, Rita Casadio, Bruno Samorì Hierarchical Mechanochemical Switches in Angiostatin; ChemBioChem 2006;7(11):1774-1782

External links


Linked-in.jpg