MEK5

MEK5, short for mitogen-activated protein kinase kinase 5, is a dual-specificity protein kinase in the MAPK signaling cascade. It functions as the upstream activator of ERK5 (also known as BMK1), phosphorylating it on its activation loop to promote signaling to the nucleus. In humans, MEK5 is encoded by the MAP2K5 gene and is expressed in multiple tissues; several isoforms can be produced by alternative splicing. MEK5 is predominantly cytoplasmic but can translocate to the nucleus upon activation.

Activation and signaling: MEK5 is activated by upstream MAP kinase kinase kinases, notably MEKK2 and MEKK3, through phosphorylation. Once active, MEK5 phosphorylates ERK5, enabling ERK5 to move into the nucleus where it engages transcription factors such as the MEF2 family and other targets. This signaling regulates gene expression related to cell growth, differentiation, survival, and stress responses.

Biological roles: MEK5–ERK5 signaling is important for embryonic development, particularly vascular development and neurogenesis. In endothelial cells, the pathway supports vascular integrity and angiogenic responses and responds to shear stress. Depending on the cellular context, MEK5–ERK5 can influence cell migration, survival, and responses to oxidative or other stresses.

Clinical significance: Dysregulation of the MEK5–ERK5 axis has been associated with cancer progression in various contexts, as well as cardiovascular and neurodegenerative disease models. Because its signaling outputs are distinct from the ERK1/2 pathway, MEK5–ERK5 remains a potential target for therapeutic intervention, with ongoing studies using genetic and pharmacological tools to dissect its roles.