Examining the Intersection of Transitional Metals and Kinase Signal Transduction Networks

检查过渡金属和激酶信号转导网络的交叉点

• 批准号: 9978887
• 负责人: Donita C Brady
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978887
• 关键词: Biochemistry; Biophysics; Cardiovascular Diseases; Cell Death; Cell Proliferation; Cell division; Cell physiology; Cells; Communication; Copper; Cues; Development; Dietary intake; Disease; Enzymes; Equilibrium; Excretory function; Failure to Thrive; Goals; Growth; Health; Hepatolenticular Degeneration; Homeostasis; Human; Impaired wound healing; Inherited; Intervention; Link; MAP Kinase Gene; MAP2K1 gene; Malignant Neoplasms; Maps; Menkes Kinky Hair Syndrome; Metabolism; Micronutrients; Molecular; Molecular Biology; Nutrient; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphotransferases; Physiology; Prevalence; Process; Proteins; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Therapeutic; Transition Elements; Work; absorption; base; biological systems; cell growth; cofactor; functional genomics; in vivo; interdisciplinary approach; mouse model; non-alcoholic fatty liver disease; novel; rare genetic disorder; response; tumorigenesis

PROJECT SUMMARY/ ABSTRACT Normal physiology relies on the precise coordination of intrinsic cues, in the form of intracellular signal transduction pathways, with extrinsic cues like nutrient availability to balance cell growth and cell death. Transition metals such as copper (Cu) are tightly regulated micronutrients that function as structural or catalytic cofactors for proteins that are critical for normal physiology and development. Aberrant Cu excretion and absorption are manifested in the extremely rare genetic diseases Wilson and Menkes, respectively. The importance of intact Cu homeostatic mechanisms to cell growth control is underscored by the stunted growth and failure to thrive associated with Cu deficiency in Menkes disease patients and the prevalence of cancer in patients with hereditary Cu overload in Wilson disease. Further, Cu is neither created nor destroyed, and therefore low Cu dietary intake may be a contributing factor in impaired wound healing, cardiovascular disease, and non-alcoholic fatty liver disease. However, the dysregulation of a handful of currently identified Cu- dependent enzymes does not fully explain the diverse growth phenotypes associated with alterations in Cu metabolism. Thus, the direct cellular pathways that respond to and or/sense Cu abundance and are integrated to influence cellular proliferation remain undefined. Recent work by our group uncovered an unexpected link between the cellular acquisition of Cu and a mitogenic signaling cascade. In response to proliferative signals, Cu contributes to the amplitude of canonical MAPK signaling through a direct interaction between Cu and the kinases MEK1 and MEK2. This is the first example of Cu directly regulating the activity of a mammalian kinase and has exposed a new signaling paradigm that directly connects Cu to signaling pathway components. Based on our expertise, our group seeks to define the Cu-responsive and -sensing kinase signal transduction pathways to determine the mechanisms by which Cu contributes to pro-proliferative cellular processes that are essential to normal proliferation and are sustained during tumorigenesis. To accomplish our goals, we will utilize a multidisciplinary approach, which includes in vivo mouse models, biochemistry, biophysics, molecular biology, functional genomics, and pharmacologic interventions. Specifically, we will: i) elucidate the molecular mechanisms and cellular contexts that underlie Cu integration into the MAPK pathway, ii) systematically map Cu utilization by pro-proliferative kinase signal transduction pathways, and iii) leverage our experimental approaches and findings to other transition metals and kinase signaling networks in normal homeostasis and cancer. Completion of these studies has the potential to establish Cu availability as an integral component of intracellular communication and elucidate the molecular mechanism underlying this unique connection. Further, identifying novel Cu-dependent kinases can be therapeutically exploited to perturb Cu availability for essential signaling pathways in cancer and other diseases settings.

项目概要/摘要 正常生理机能依赖于细胞内信号形式的内在线索的精确协调 转导途径，具有平衡细胞生长和细胞死亡的营养可用性等外在线索。 铜 (Cu) 等过渡金属是受到严格调控的微量营养素，具有结构或催化作用 对正常生理和发育至关重要的蛋白质的辅助因子。铜排泄异常和 吸收分别表现在极其罕见的遗传病威尔逊病和门克斯病中。这 生长发育迟缓强调了完整的铜稳态机制对细胞生长控制的重要性 门克斯病患者的发育迟缓与铜缺乏有关，以及癌症的患病率 威尔逊病遗传性铜超载患者。此外，Cu既不会被创造也不会被破坏，并且 因此，低铜饮食摄入量可能是伤口愈合受损、心血管疾病、 和非酒精性脂肪肝。然而，目前发现的少数铜的失调 依赖酶并不能完全解释与 Cu 变化相关的不同生长表型 代谢。因此，响应和/或感测铜丰度并整合的直接细胞途径 影响细胞增殖的作用仍不清楚。我们小组最近的工作发现了一个意想不到的联系 Cu 的细胞获取和有丝分裂信号级联反应之间的关系。为了响应增殖信号， Cu 通过 Cu 与 激酶 MEK1 和 MEK2。这是铜直接调节哺乳动物激酶活性的第一个例子 并揭示了一种新的信号传导范式，可直接将 Cu 与信号传导通路组件连接起来。基于 根据我们的专业知识，我们的团队致力于定义 Cu 响应和感应激酶信号转导 确定铜促进细胞增殖过程的机制的途径 对正常增殖至关重要，并在肿瘤发生过程中持续存在。为了实现我们的目标，我们将 利用多学科方法，包括体内小鼠模型、生物化学、生物物理学、分子生物学 生物学、功能基因组学和药理学干预。具体来说，我们将： i) 阐明 Cu 整合到 MAPK 途径的分子机制和细胞环境，ii) 系统地绘制促增殖激酶信号转导途径对铜的利用情况，以及 iii) 将我们的实验方法和发现应用于其他过渡金属和激酶信号传导 正常稳态和癌症中的网络。完成这些研究有可能建立铜 可用性作为细胞内通讯的一个组成部分并阐明分子机制 这种独特联系的基础。此外，鉴定新的铜依赖性激酶可以在治疗上 被用来扰乱癌症和其他疾病环境中重要信号通路的铜的可用性。