Components of Translation in Signal Transduction

描述（由申请人提供）：本项目主要研究两种人氨基酰tRNA合成酶的细胞信号转导活性。虽然这两种酶是蛋白质合成所必需的，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没有活性，可能被视为原细胞因子。通过选择性剪接或蛋白水解，产生具有有效活性的天然片段。这些片段作为血管生成的阴阳调节剂——一个是促血管生成，而另一个是抗血管生成。最强调的是人类色氨酸- trna合成酶和称为T2-TrpRS的片段，这是一种有效的血管抑制剂。在最近完成的工作中，该实验室已经鉴定了细胞受体，阐明了一些下游信号事件，并确定了t2 - trpr的高分辨率x射线结构。未来工作的目标是进一步阐述t2 - trpr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迷你tyrrs（酪氨酸- trna合成酶片段）的情况下，其结构已经确定，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。控制血管生长对抑制血管化肿瘤的发展至关重要。血管抑制剂t2 - trpr的研究可以使我们对其有充分的了解，从而保证其用于治疗特定癌症的发展。这种可能性特别有吸引力，因为t2 - trpr似乎通过独特的途径起作用，并且有机会将其与通过其他途径起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.