Abstract
The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.
Highlights
Bone health critically depends on a balance between the opposing actions of boneforming osteoblasts produced by differentiation of mesenchymal stem cells (MSCs) and bone-resorbing osteoclasts differentiating from the myeloid lineage [79]
We have shown that both BRAF- and NRAS-mutant melanoma cell lines significantly upregulated ERK5 signaling when subjected to MEKi using trametinib, selumetinib, binimetinib or cobimatinib, or ERK1/2 inhibition (ERKi) using GDC-0994 [37] (Figure 5)
ERK5: Structure and Regulation or ERK1/2 (ERKi) trigger compensatory activation of the MEK5/ERK5 pathway via stimulation of Structurally, ERK5 differs from its closest relative, ERK2, and other mitogenactivated protein kinases (MAPK) by the different receptor tyrosine kinases (RTK) [37,119,120] in order to allow tumor cells to escape MAPKipresence of a unique C-terminal extension
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. MAPK pathways are activated by a wide variety of stimuli, including mitogens, cytokines, stress, and UV radiation [1]. They all comprise a three-tiered signaling module with MAPK kinase kinases (MAP3Ks or MEKKs) at the top of the cascade. MAPKs shuttle into the nucleus where they phosphorylate diverse substrates, including transcription factors, co-regulators and chromatin proteins. These activating or inactivating phosphorylation events regulate cell survival, proliferation, migration, differentiation, and angiogenesis, as well as apoptotic signaling (reviewed in [1,2,3]). We summarize its emerging role as a drug resistance pathway in various cancers
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