MEKK2/3-MEK5 Interaction/Activation/ERK5 Pathway(RMI)

MEKK2/3-MEK5 相互作用/激活/ERK5 通路(RMI)

• 批准号: 7021866
• 负责人: Bruce D Cuevas
• 金额: $ 7.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021866
• 关键词: antiinflammatory agents; bioassay; biotechnology; chemical registry /resource; drug discovery /isolation; drug screening /evaluation; fluorescence resonance energy transfer; fluorescent dye /probe; high throughput technology; kinase inhibitor; method development; mitogen activated protein kinase; phosphorylation; protein binding; protein protein interaction; scintillation counter; small molecule

DESCRIPTION (provided by applicant): In the mitogen-activated protein kinase (MAPK) cell signaling system, MKKKs phosphorylate and activate MKKs, which in turn phosphorylate and activate MAPKs (JNK, ERK1/2, p38, and ERK5). For example, the MKKK MEKK2 regulates the JNK signaling pathway, whereas the closely related MEKK3 controls p38 activity, thus establishing distinct cellular functions. However, both MEKK2 and MEKK3 regulate a third MAPK pathway resulting in the activation of ERK5, and consequently regulate ERK5-dependent gene expression. The MEKK2/3-MEK5 pathway is the predominant MAPK module to control ERK5 activation. ERK5 is activated by a variety of growth factors and stress stimuli, and genetic approaches have demonstrated that ERK5 is involved in angiogenesis and cardiac hypertrophy. MEKK2/3 and MEK5 interact by their N-terminal PB1 (Phox/Bem1p) domains that are unique among known MAPK module components, and this interaction regulates activation of MEK5 ERK5, but not JNK or p38. Importantly, while the signals that influence MAPK activation can be diverse, ERK5 signaling converges at the MEKK2/3-MEK5 nexus; a function mediated by PB1 domain interaction. This essential interaction therefore presents a unique opportunity to specifically block ERK5 signaling. We propose to develop an assay for ERK5 pathway signaling based on this PB1 domain interaction that will facilitate high throughput screening of potential ERK5 signaling inhibitors that function through disrupting PB1 domain association. Targeting MEKK2/3- MEK5 interaction by small molecule inhibitors will markedly disrupt ERK5 activation and selectively inhibit stimulus-specific activation of cytokine expression in multiple cell types, and thus provide new opportunities for therapeutic intervention in diseases involving inflammation.

描述（由申请人提供）：在有丝分裂原激活的蛋白激酶（MAPK）细胞信号系统中，MKKKS磷酸化和激活MKK，进而激活MKK，这又磷酸化并激活MAPKS（JNK，ERK1/2，P38和ERK5）。例如，MKKK MEKK2调节JNK信号通路，而密切相关的MEKK3控制p38活性，从而建立了不同的细胞功能。但是，MEKK2和MEKK3都调节了第三个MAPK途径，导致ERK5的激活，因此调节ERK5依赖性基因表达。 MEKK2/3-MEK5途径是控制ERK5激活的主要MAPK模块。 ERK5被多种生长因子和应力刺激激活，遗传方法表明ERK5参与血管生成和心脏肥大。 MEKK2/3和MEK5通过其N末端PB1（PHOX/BEM1P）域相互作用，它们在已知的MAPK模块组件之间是独一无二的，并且这种相互作用调节MEK5 ERK5的激活，但不能调节JNK或P38的激活。重要的是，尽管影响MAPK激活的信号可能是多种多样的，但ERK5信号传导在MEKK2/3-MEK5 NEXUS上收敛。由PB1域相互作用介导的函数。因此，这种基本相互作用为特定阻止ERK5信号传导提供了独特的机会。我们建议基于这种PB1结构域的相互作用开发ERK5途径信号传导的测定法，该测定将促进通过破坏PB1域关联起作用的潜在ERK5信号抑制剂的高吞吐量筛选。针对小分子抑制剂靶向MEKK2/3-MEK5相互作用将显着破坏ERK5激活，并有选择地抑制多种细胞类型中细胞因子表达的刺激特异性激活，从而为涉及炎症的疾病中的治疗干预提供了新的机会。