Kinase-dependent Regulation of Metabolic Enzymes

项目摘要 促生长信号和代谢变化是其发育的重要机制 以及癌症和其他增殖性疾病的进展，但介导相互作用的机制 这些关键的调控事件之间的关系还知之甚少。最近，我们发现了一个令人惊讶和新颖的 通过生长因子调节的酪氨酸激酶Ack控制核苷酸合成的机制。确认控制 CTP合成中的限速酶的活性，CTP合成酶（CTPS）通过调节组装， 由CTPS组成的酶活性大分子结构的分解和速率限制 鸟嘌呤核苷酸生物合成酶。我们称这些结构为鳍状结构， 核苷酸合成根据这些初步数据，我们的中心假设是， 核苷酸池触发Ack依赖性FINS组装以刺激平衡的嘌呤和嘧啶 生物合成在这里，我们将测试这一假设使用机械生化研究，将随后 在果蝇体内验证，我们已经证明了卵子发生中对该途径的关键要求。的 工作将阐明两个重要领域，信号和代谢，通过动态交叉 大分子蛋白质组装体的组装。目前使用的抑制IMPDH和触发FINS的药物 在患者中的组装突出了这项工作的重要性及其发现其他药物的潜力。 免疫抑制以及抗肿瘤和抗寄生虫干预的治疗途径。

Project Summary Growth-promoting signals and changes in metabolism are important mechanisms in the development and progression of cancer and other proliferative disorders, but the mechanisms that mediate interactions between these key regulatory events are poorly understood. Recently, we discovered a surprising and novel mechanism for control of nucleotide synthesis by Ack, a growth-factor regulated tyrosine kinase. Ack controls the activity of the rate-limiting enzyme in CTP synthesis, CTP synthase (CTPS) by regulating the assembly and disassembly of an enzymatically active macromolecular structure composed of CTPS and the rate-limiting enzyme in guanine nucleotide biosynthesis, IMPDH. We call these structures FINS for filaments involved in nucleotide synthesis. Based on this preliminary data, our central hypothesis is that inadequate cellular nucleotide pools trigger Ack-dependent FINS assembly to stimulate balanced purine and pyrimidine biosynthesis. Here, we will test this hypothesis using mechanistic biochemical studies that will be subsequently validated in vivo in Drosophila, where we have shown a critical requirement for this pathway in oogenesis. The work will illuminate how two important fields, signaling and metabolism, intersect through the dynamic assembly of a macromolecular protein assembly. The current use of drugs that inhibit IMPDH and trigger FINS assembly in patients highlights the importance of this work and its potential for discovery of additional therapeutic avenues for immuosuppression as well as anti-neoplastic and anti-parasitic interventions.