This project focuses on the cell-signaling activities of two human aminoacyl tRNA synthetases. Although these two enzymes are essential for protein synthesis, they also acquired expanded functions that regulate growth of blood vessels, that is, regulate angiogenesis. In both instances, the native enzymes have not active in angiogenesis and may be viewed as procytokines. Through alternative splicing or proteolysis, natural fragments are created that have potent activities. These fragments act as yin-yang regulators of angiogenesis-one being pro-angiogenic, while the other is anti-angiogenic. Most emphasis is placed on human tryptophanyl-tRNA synthetase and a fragment known as T2-TrpRS, which is a potent angiostatic agent. In recently completed work, the laboratory has identified the cellular receptor, elucidated some downstream signaling events, and determined a high-resolution x-ray structure of T2-TrpRS.
The aims of future work are to further elaborate on the pathway through which T2-TrpRS inhibits angiogenesis, to investigate the mechanism by which it is exported from endothelial cells, and to carry out structure-based design of variants to better understand how it interacts with a cellular receptor. In the case of the pro-angiogenic cytokine mini TyrRS-a fragment of tyrosyl-tRNA synthetase-the structure has been determined and the receptor has also been identified. Future work focuses on a structure-based approach to understanding the mechanism of cytokine activation. The control of blood vessel growth is essential to arrest development of vascularized tumors. Work on the angiostatic T2-TrpRS can lead to sufficient understanding to warrant its development for treatment of specific cancers. This possibility is particularly attractive because of the unique pathway through which T2-TrpRS appears to work and the opportunity to combine it with other anti-cancer therapies that act through other pathways. ? ? ?
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