Structure and function of collagen-derived endostatin inhibitors of angiogenesis.
Endostatins are inhibitors of endothelial cell migration and angiogenesis and have been shown to reduce tumor growth in animal models. They are derived from the nontriplehelical C-terminal NC1 domains of collagens XV and XVIII, which are released proteolytically in trimeric form and further converted to monomeric endostatins of about 20 kDa. Both endostatin isoforms share a compact globular fold, but differ in certain binding properties for proteins and cells, as well as in tissue distribution. Differences in activity were found between NC1 domains and endostatins and are related to the oligomerization state. Endostatin effects are not restricted to endothelial cells, but also control renal epithelial cells and neuronal guidance in C. elegans. Cellular receptors are still insufficiently characterized and include for endostatin-XVIII heparan sulfate proteoglycans. Receptor engagement elicits various downstream effects including tyrosine kinase and gene activation. Much remains to be learned, however, about details of the signal transduction cascades and how they interfere with pro-angiogenic factors under physiological conditions and during therapeutic treatment.
Sasaki
Takako
T
Max-Planck-Institut für Biochemie, Martinsried, Germany.
Hohenester
Erhard
E
Timpl
Rupert
R
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D043170:Collagen Type XVIII; D043169:Endostatins; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen