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.

项目摘要/摘要 正常的生理学依赖于内在提示的精确协调，以细胞内信号的形式 转导途径，具有诸如养分可用性之类的外部线索，以平衡细胞生长和细胞死亡。 过渡金属（例如铜（CU））是紧密调控的微量营养素，起着结构或催化作用 对于正常生理和发育至关重要的蛋白质的辅助因子。异常的铜排泄和 吸收分别体现在威尔逊和梅克斯的极为罕见的遗传疾病中。这 完整的Cu稳态机制对细胞生长控制的重要性是由发育迟缓的生长强调的 以及未能与Menkes病患者的CU缺乏症相关的壮成长和癌症患病率 威尔逊疾病中遗传性CU超负荷的患者。此外，Cu既不是创造也不破坏的，并且 因此，低铜饮食摄入量可能是伤口愈合受损，心血管疾病的促成因素 和非酒精性脂肪肝病。但是，少数当前确定的Cu-的失调 依赖性酶不能完全解释与Cu改变相关的不同生长表型 代谢。因此，对响应和/感知铜的直接细胞途径并被整合 影响细胞增殖仍然不确定。我们小组的最新工作发现了一个意外的链接 在Cu的细胞获取与有丝分裂信号级联之间。响应增生信号， CU通过CU与CU之间的直接相互作用有助于规范MAPK信号的振幅 激酶MEK1和MEK2。这是CU直接调节哺乳动物激酶活性的第一个例子 并暴露了一种新的信号范式，该范式将CU直接连接到信号通路组件。基于 在我们的专业知识上，我们的小组试图定义CU响应和传感激酶信号转导 确定Cu促进促增殖性细胞过程的机制的途径 对正常增殖必不可少的，在肿瘤发生过程中持续。为了实现我们的目标，我们将 利用多学科方法，其中包括体内小鼠模型，生物化学，生物物理学，分子 生物学，功能基因组学和药理干预措施。具体来说，我们将：i）阐明 Cu整合到MAPK途径的基础的分子机制和细胞环境，II） 系统地通过促增强激酶信号转导途径和III绘制CU利用率 利用我们的实验方法和发现为其他过渡金属和激酶信号传导 正常稳态和癌症的网络。这些研究的完成有可能建立Cu 可用性是细胞内通信不可或缺的组成部分，并阐明了分子机制 在这种独特的联系的基础上。此外，鉴定新颖的Cu依赖性激酶可以治疗 利用cu摄取癌症和其他疾病设置的基本信号通路的可用性。