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

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于凋亡和炎症活化方面发挥关键作用。在生理学上，ERK 5被通过内皮的血流产生的连续层流剪切应力激活，其在维持内皮完整性中起核心作用并赋予对血管炎性疾病的保护。在其他细胞中，ERK 5也可以被促有丝分裂刺激激活，并在肿瘤形成（包括皮肤癌发生）中发挥鲜为人知的功能，我们迄今未发表的工作确定了内皮细胞中MEK5/ERK 5通路和FoxO叉头转录因子之间的新型抑制性相互作用。FoxO作为生长因子敏感的肿瘤抑制因子，其在小鼠中的损失导致背景特异性肿瘤发生，特别是表现在血管瘤和T细胞淋巴瘤的发生率增加。此外，它们通过促进细胞凋亡和炎症在血管炎性疾病如动脉粥样硬化中发挥有害作用。我们的初步研究结果提示，ERK 5介导的FoxO抑制可能参与了先前提出的ERK 5的血管保护和致瘤作用。特别地，我们将分析组成性或生理性切应力介导的ERK 5活化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FoxO活性在其他细胞中的有效调节机制。此外，我们将研究我们的发现在肿瘤发生和血管功能障碍方面的功能相关性。使用各种肿瘤细胞，我们将分析所观察到的ERK 5对FoxOs的抑制是否在不同细胞类型中是保守的，并且是否可能代表一种新的致癌机制，该机制可能被潜在地用于治疗。此外，我们将评估某些病理条件，如糖尿病相关的高血糖症可能会导致观察到的ERK 5和FoxO之间的抑制性相互作用的功能障碍，触发FoxO重新激活，从而增加内皮细胞凋亡和inflammation.From我们的研究，我们预计一个明确的答案，如果单一或多种机制参与观察到的ERK 5对FoxO依赖的基因表达的抑制作用。此外，我们希望确定新的靶结构，用于血管疾病中有害FoxO激活的潜在治疗干预，并预测ERK 5介导的FoxO抑制是否可能代表一种新的致癌机制。

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mitogenic stimuli and exerts a poorly understood function in tumor formation including skin carcinogenesis.Our so far unpublished work identified a novel inhibitory interaction between the MEK5/ERK5 pathway and FoxO forkhead transcription factors in endothelial cells.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.