Mitogen-activated protein kinase 7 (ERK5) (ERK5)

Mitogen-activated protein kinase 7 (MAPK7), commonly known as ERK5 or Big MAP kinase 1 (BMK1), is a unique member of the mitogen-activated protein kinase family. It is distinguished by its large size, nearly double that of other MAPKs, due to a unique C-terminal tail that contains a transcriptional activation domain (TAD) and a nuclear localization signal. ERK5 is activated by the upstream kinase MEK5 in response to various stimuli, including growth factors, cytokines, and mechanical stresses like fluid shear stress. Once activated, ERK5 regulates critical cellular processes such as proliferation, survival, and differentiation by phosphorylating downstream targets and directly acting as a transcriptional co-activator. In disease, ERK5 is frequently overexpressed or hyperactivated in various cancers, including breast, prostate, and lung cancer, where it promotes tumor growth, metastasis, and resistance to therapy. Consequently, it has emerged as a promising therapeutic target, though the development of effective inhibitors is challenged by the protein's dual kinase and transcriptional functions and its essential role in maintaining cardiovascular health.

Other names

Big MAP kinase 1BMK1MAPK7PRKM7Extracellular signal-regulated kinase 5

ERK5 inhibitors primarily target the N-terminal kinase domain to block its catalytic activity, thereby preventing the phosphorylation of downstream substrates such as MEF2. Advanced therapeutic approaches also include the use of proteolysis-targeting chimeras (PROTACs) to induce the degradation of the entire ERK5 protein, addressing both its kinase and transcriptional functions.