Kinase-dependent Regulation of Metabolic Enzymes

 描述(申请人提供)：促进生长的信号和新陈代谢的变化是癌症和其他增殖性疾病发生和发展的重要机制，但调节这些关键调控事件之间相互作用的机制尚不清楚。最近，我们发现了一种令人惊讶的新机制，通过Ack来控制核苷酸合成，Ack是一种生长因子调节的酪氨酸激酶。ACK通过调节CTP合成限速酶CTP合成酶(CTPS)和鸟嘌呤核苷酸生物合成限速酶IMPDH组成的具有酶活性的大分子结构的组装和分解来控制CTP合成限速酶的活性。我们称这些结构为参与核苷酸合成的细丝的鳍。基于这些初步数据，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，以刺激嘌呤和嘧啶的平衡生物合成。在这里，我们将使用机制生化研究来验证这一假说，这些研究随后将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。这项工作将阐明两个重要的领域，信号和新陈代谢，如何通过大分子蛋白质组装的动态组装而相交。目前抑制IMPDH和触发FINS组装的药物在患者中的使用突显了这项工作的重要性，以及它发现免疫抑制以及抗肿瘤和抗寄生虫干预的其他治疗途径的潜力。

 DESCRIPTION (provided by applicant): 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.