Components of Translation in Signal Transduction

描述(申请人提供)：本项目重点研究两种人氨基酰tRNA合成酶的细胞信号活性。虽然这两种酶对蛋白质合成是必不可少的，但它们也获得了调节血管生长的扩展功能，即调节血管生成。在这两种情况下，天然酶在血管生成中并不活跃，可能被视为原细胞因子。通过选择性剪接或蛋白质降解，产生具有强大活性的天然片段。这些片段充当血管生成的阴阳调节器--一个是促血管生成的，另一个是反血管生成的。大部分的重点放在人类色氨酰-tRNA合成酶和被称为T2-TrpRS的片段上，T2-TrpRS是一种有效的血管抑制剂。在最近完成的工作中，实验室已经确定了细胞受体，阐明了一些下游信号事件，并确定了T2-TrpRS的高分辨率X射线结构。未来工作的目标是进一步阐明T2-TrpRS抑制血管生成的途径，研究其从内皮细胞输出的机制，并进行基于结构的突变体设计，以更好地了解它如何与细胞受体相互作用。在促血管生成细胞因子Mini TyrRS的情况下-酪氨酰-tRNA合成酶的片段-结构已经确定，受体也已经确定。未来的工作重点是基于结构的方法来理解细胞因子激活的机制。控制血管生长是阻止血管化肿瘤发展的关键。对血管抑制T2-TrpRs的研究可以带来足够的了解，以保证其开发用于特定癌症的治疗。这种可能性特别有吸引力，因为T2-TrpRS似乎通过独特的途径发挥作用，并有机会将其与通过其他途径发挥作用的其他抗癌疗法结合起来。

DESCRIPTION (provided by applicant): 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.