Kinase-dependent Regulation of Metabolic Enzymes

代谢酶的激酶依赖性调节

基本信息

批准号：
9278189
负责人：
JEFFREY R PETERSON
金额：
$ 36.14万
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278189
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 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 public health relevance reconstitution response small molecule inhibitor targeted treatment tumor progression

项目摘要

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.

描述（由适用提供）：促进生长信号和代谢的变化是癌症发展和发展和其他增殖疾病的重要机制，但是介导这些关键调节事件之间相互作用的机制知之甚少。最近，我们发现了一种令人惊讶的和新颖的机制，用于控制一种生长因子调节的酪氨酸激酶ACK核苷酸合成。 ACK通过调节CTP合成，CTP合酶（CTP）中的速率限制酶的活性，通过调节由CTPS组成的酶活性大分子分子结构的组装和拆卸，以及由鸟嘌呤核苷酸生物合成中的速率限制酶组成。我们将这些结构鳍称为参与核苷酸合成的细丝。基于此初步数据，我们的中心假设是细胞核ri池不足触发ACK依赖的鳍片组件以刺激平衡的购买和嘧啶生物合成。在这里，我们将使用机械生化研究来检验这一假设，该研究将随后在果蝇中的体内进行验证，在那里我们在卵子发生中对此途径显示了关键要求。这项工作将通过大分子蛋白质组装的动态组装来阐明两个重要的信号传导和代谢如何相交。目前使用抑制IMPDH和触发鳍片组装的药物在患者中的使用凸显了这项工作的重要性及其在发现额外的治疗途径中用于免疫抑制以及反塑性和抗寄生虫干预措施的潜力。