Kinase-dependent Regulation of Metabolic Enzymes

项目摘要 促生长信号和代谢变化是发育过程中的重要机制 癌症和其他增殖性疾病的进展，但调节相互作用的机制 在这些关键监管事件之间，人们对此知之甚少。最近，我们发现了一个令人惊讶的新奇 Ack控制核苷酸合成的机制，Ack是生长因子调节的酪氨酸激酶。确认控制 CTP合成中的限速酶CTP合成酶(CTPS)通过调节组装和 具有酶活性的CTPS大分子结构的拆解及其限速 鸟嘌呤核苷酸生物合成中的酶我们称这些结构为细丝的鳍状物 核苷酸合成。基于这个初步数据，我们的中心假设是，不充分的细胞 核苷酸池触发Ack依赖的FINS组装以刺激平衡的嘌呤和嘧啶 生物合成。在这里，我们将使用随后将进行的机械性生物化学研究来检验这一假设 在果蝇体内得到验证，我们已经证明了这一途径在卵子发生中的关键要求。这个 这项工作将阐明两个重要的领域，信号和新陈代谢，如何通过动态 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 患者的装配强调了这项工作的重要性及其发现其他 免疫抑制的治疗途径以及抗肿瘤和抗寄生虫干预。

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.