A fragment of human TrpRS as a potent antagonist of ocular angiogenesis.
Pathological angiogenesis contributes directly to profound loss of vision associated with many diseases of the eye. Recent work suggests that human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) link protein synthesis to signal transduction pathways including angiogenesis. In this study, we show that a recombinant form of a COOH-terminal fragment of TrpRS is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in a mouse model and of naturally occurring retinal angiogenesis in the neonatal mouse. The angiostatic activity is dose-dependent in both systems. The recombinant fragment is similar in size to one generated naturally by alternative splicing and can be produced by proteolysis of the full-length protein. In contrast, the full-length protein is inactive as an antagonist of angiogenesis. These results suggest that fragments of TrpRS, as naturally occurring and potentially nonimmunogenic anti-angiogenics, can be used for the treatment of neovascular eye diseases.
Otani
Atsushi
A
Department of Cell Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Slike
Bonnie M
BM
Dorrell
Michael I
MI
Hood
John
J
Kinder
Karen
K
Ewalt
Karla L
KL
Cheresh
David
D
Schimmel
Paul
P
Friedlander
Martin
M
D017398:Alternative Splicing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D012171:Retinal Vessels / Q000502:physiology*; D015398:Signal Transduction; D014369:Tryptophan-tRNA Ligase / Q000737:chemistry* / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D003094:Collagen; D014369:Tryptophan-tRNA Ligase