Kinase-dependent Regulation of Metabolic Enzymes

代谢酶的激酶依赖性调节

• 批准号: 9145229
• 负责人: JEFFREY R PETERSON
• 金额: $ 34.92万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 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/9145229
• 关键词: Actins; Anabolism; Architecture; Bacteria; Biochemical; Biological Process; Cell Proliferation; Cells; Coupled; Cultured Cells; Cytoskeletal Proteins; Data; Development; Disease; Drosophila genus; Drug Targeting; Drug usage; Enzymes; Equilibrium; Event; Feedback; Filament; Fluorescence Microscopy; Funding; Goals; Grant; Growth; Guanine Nucleotides; Health; Human; Immunosuppressive Agents; In Vitro; Individual; Inosine Monophosphate; Intervention; Length; Life; Link; Malignant Neoplasms; Mammalian Cell; Measures; Mediating; Metabolic; Metabolism; Molecular; Molecular Structure; Mutation; Nucleotide Biosynthesis; Nucleotides; Nutrient; Oogenesis; Organism; Oxidoreductase; Pathway interactions; Patients; 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; neoplastic; novel; nucleotide metabolism; polymerization; reconstitution; response; small molecule inhibitor; targeted treatment; tumor progression

 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（由申请人提供）：促生长信号和代谢变化是癌症和其他增殖性疾病发生和进展的重要机制，但对介导这些关键调控事件之间相互作用的机制知之甚少。最近，我们发现了一个令人惊讶的和新的机制来控制核苷酸的合成由Ack，生长因子调节的酪氨酸激酶。Ack通过调节由CTP合成中的限速酶CTP合酶（CTPS）和鸟嘌呤核苷酸生物合成中的限速酶IMPDH组成的酶活性大分子结构的组装和分解来控制CTP合成中的限速酶CTP合酶（CTPS）的活性。我们称这些结构为FINS，是指参与核苷酸合成的细丝。基于这些初步的数据，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，刺激平衡的嘌呤和嘧啶的生物合成。在这里，我们将测试这一假设，使用机制的生化研究，随后将在果蝇体内验证，在那里我们已经显示了卵子发生的这一途径的关键要求。这项工作将阐明两个重要的领域，信号和代谢，交叉通过动态组装的大分子蛋白质组装。目前使用的药物，抑制IMPDH和触发FINS组装的患者突出了这项工作的重要性，其潜在的发现额外的治疗途径，免疫抑制以及抗肿瘤和抗寄生虫干预。