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

• Applicant: Professor Dr. Marc Schmidt
• Subject Area: Dermatology ; Biochemistry ; Hematology, Oncology ; Cardiology, Angiology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314298055

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mitogenic stimuli and exerts a poorly understood function in tumor formation including skin carcinogenesis.Our so far unpublished work identified a novel inhibitory interaction between the MEK5/ERK5 pathway and FoxO forkhead transcription factors in endothelial cells.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

• DFG Programme: Research Grants