Crosstalk between the MEK5/ERK5 and PKB/FoxO pathways: Underlying mechanism and its relevance for vasoprotection and tumorigenesis

MEK5/ERK5 和 PKB/FoxO 通路之间的串扰：潜在机制及其与血管保护和肿瘤发生的相关性

• 批准号: 314298055
• 负责人: Professor Dr. Marc Schmidt
• 金额: --
• 依托单位: Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314298055?language=en
• 关键词: Crosstalk; between; MEK5; ERK5; PKB

The MEK5/ERK5 cascade is a major protective signaling module that is essential for vascular development. In adult vessels it furthermore plays a critical role for the maintenance of endothelial barrier function and protects endothelial cells from apoptosis and inflammatory activation. Physiologically, ERK5 is activated by the continuous laminar shear stress generated by the blood flow through the endothelium, which plays a central role in sustaining endothelial integrity and confers protection from vascular inflammatory diseases. In other cells ERK5 can also be activated by mitogenic stimuli and exerts a poorly understood function in tumor formation including skin carcinogenesis.Our so far unpublished work identified a novel inhibitory interaction between the MEK5/ERK5 pathway and FoxO forkhead transcription factors in endothelial cells. FoxOs act as growth-factors sensitive tumor-suppressors, which loss in mice results in context-specific tumorigenesis that especially manifests in an increased occurrence of hemangiomas and T-cell lymphomas. Moreover, they exert a detrimental function in vascular inflammatory diseases such as atherosclerosis by promoting apoptosis and inflammation. Our preliminary data raise the possibility that ERK5-mediated FoxO repression might contribute to the previously proposed vasoprotective and tumorigenic action of ERK5.Here we address the molecular mechanism(s) of this newly identified negative circuit observed in endothelial cells. Particularly we will analyze if constitutive or physiological shear stress-mediated ERK5 activation limits FoxO activity by altering its localization, phosphorylation, acetylation or protein-protein interaction in endothelial cells, which all represent valid regulatory mechanisms of FoxO activity in other cells.In addition we will study the functional relevance of our findings in the context of tumorigenesis and vascular dysfunction.Using various tumor cells including cell lines derived from cutaneous T-cell lymphoma, melanoma or squamous cell carcinoma we will analyze whether the observed inhibition of FoxOs by ERK5 is conserved among different cell types and might represent a novel oncogenic mechanism that could potentially be exploited for therapy. In addition we will evaluate if certain pathological conditions such as diabetes-associated hyperglycemia might result in dysfunction of the observed inhibitory interaction between ERK5 and FoxOs triggering FoxO re-activation and consequently augmentation of endothelial apoptosis and inflammation.From our studies we anticipate a clear answer if single or multiple mechanisms are involved in the observed inhibitory action of ERK5 on FoxO-dependent gene expression. Moreover, we hope to identify novel target structures for a potential therapeutic intervention with harmful FoxO activation in vascular diseases and anticipate an answer if ERK5-mediated FoxO inhibition may represent a novel oncogenic mechanism.

MEK5/ERK5级联是一个重要的保护性信号模块，对血管发育至关重要。在成人血管中，它还在维持内皮屏障功能和保护内皮细胞免受凋亡和炎症激活方面发挥关键作用。从生理上讲，ERK5是由血流通过内皮产生的持续层流剪应力激活的，在维持内皮完整性和保护血管免受炎症性疾病的保护方面发挥着核心作用。在其他细胞中，ERK5也可以被有丝分裂刺激激活，并在包括皮肤癌在内的肿瘤形成中发挥着鲜为人知的功能。到目前为止，我们尚未发表的工作在内皮细胞中发现了MEK5/ERK5通路和FoxO叉头转录因子之间的新的抑制相互作用。FOXO作为生长因子敏感的肿瘤抑制因子，在小鼠体内的缺失会导致特定背景的肿瘤发生，特别是在血管瘤和T细胞淋巴瘤的发生率增加方面。此外，它们通过促进细胞凋亡和炎症，在动脉粥样硬化等血管炎症性疾病中发挥有害作用。我们的初步数据提出了ERK5介导的FoxO抑制可能参与了先前提出的ERK5的血管保护和致瘤作用。在这里，我们讨论了在内皮细胞中观察到的这种新发现的负回路的分子机制(S)。特别是，我们将分析结构性或生理性剪切力介导的ERK5激活是否通过改变其在内皮细胞中的定位、磷酸化、乙酰化或蛋白质-蛋白质相互作用来限制FoxO活性，这些都代表了其他细胞中FoxO活性的有效调节机制。此外，我们还将研究我们的发现在肿瘤发生和血管功能障碍背景下的功能相关性。我们将使用各种肿瘤细胞，包括皮肤T细胞淋巴瘤、黑色素瘤或鳞癌细胞系，分析ERK5对FoxO活性的抑制是否在不同类型的细胞中保持不变，并可能代表一种潜在的可用于治疗的新的致癌机制。此外，我们将评估某些病理条件，如糖尿病相关性高血糖，是否会导致已观察到的ERK5与FoxO之间的抑制相互作用功能障碍，从而触发FoxO重新激活，从而增强内皮细胞的凋亡和炎症。从我们的研究中，我们期待着一个明确的答案，即ERK5对FoxO依赖的基因表达的抑制作用是单一机制还是多机制参与。此外，我们希望为血管疾病中有害的FoxO激活的潜在治疗干预寻找新的靶点结构，并期待ERK5介导的FoxO抑制可能代表一种新的致癌机制的答案。