Kinase-dependent Regulation of Metabolic Enzymes

代谢酶的激酶依赖性调节

基本信息

批准号：
9700784
负责人：
JEFFREY R PETERSON
金额：
$ 3.68万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9700784
关键词：
Actins Anabolism Antineoplastic Agents Antiparasitic Agents Architecture Bacteria Biochemical Biological Process Cell Proliferation Cells Coupled Cultured Cells Cytoskeletal Proteins Data Development Disease Drosophila genus Drug Targeting Drug usage Enzymes Event Feedback Filament Fluorescence Microscopy Funding Goals Grant Growth Growth Factor Guanine Nucleotides Human Immunosuppressive Agents In Vitro Individual Inosine Monophosphate Intervention Length Link Malignant Neoplasms Mammalian Cell Measures Mediating Metabolic Metabolism Molecular Molecular Structure Mutation Nucleotide Biosynthesis Nucleotides Nutrient Nutrient Depletion Oogenesis Organism Oxidoreductase Pathway interactions Patients Pharmacology Phosphorylation Phosphotransferases Physiological Polymers Prevalence Process Protein Dynamics Protein Tyrosine Kinase Proteins Purines Pyrimidine Recombinant Proteins Regulation Role Signal Pathway Signal Transduction Structure Supporting Cell Testing Therapeutic Therapeutic Intervention Tubulin Tyrosine Work Yeasts base cancer therapy cell growth genetic approach in vivo insight knock-down macromolecule mutant novel nucleotide metabolism polymerization reconstitution response small molecule inhibitor targeted treatment tumor progression

项目摘要

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.

项目摘要增长信号和代谢的变化是发展的重要机制癌症和其他增生性疾病的进展，但是介导相互作用的机制在这些关键的监管事件之间，人们理解的。最近，我们发现了一个令人惊讶和新颖的通过ACK控制核苷酸合成的机制，ACK是一种生长因素调节的酪氨酸激酶。 ACK控件 CTP合成，CTP合酶（CTP）中限速酶的活性通过调节组件和由CTP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中的酶，IMPDH。我们将这些结构鳍称为涉及的细丝核苷酸合成。基于此初步数据，我们的中心假设是细胞不足核苷酸池触发ACK依赖性鳍片组件以刺激平衡的嘌呤和嘧啶生物合成。在这里，我们将使用机械生化研究检验这一假设在果蝇的体内验证，我们在卵子发生中显示了对该途径的关键要求。这工作将阐明两个重要领域的信号传导和代谢如何通过动态相交大分子蛋白质组装的组装。当前使用抑制IMPDH并触发鳍的药物的使用患者的组装强调了这项工作的重要性及其发现额外的潜力用于免疫抑制以及抗肿瘤和抗寄生虫干预措施的治疗途径。