BMK1

BMK1, also known as Big MAP kinase 1, is a protein kinase of the mitogen-activated protein kinase (MAPK) family. In humans it is encoded by the MAPK7 gene and is commonly referred to as ERK5 (extracellular signal-regulated kinase 5). It features an N-terminal kinase domain and a long C-terminal tail that contains a transcriptional activation domain.

Activation of ERK5 requires dual phosphorylation within the activation loop at a threonine and tyrosine in the TEY motif by the dual-specificity kinase MEK5. Upstream activation can be triggered by growth factors, osmotic or oxidative stress, and fluid shear stress; MEK5 itself is activated by several MAP kinase kinase kinases (MAP3Ks), including MEKK2/3. Once activated, ERK5 can phosphorylate a range of substrates, including transcription factors of the MEF2 family, leading to changes in gene expression. ERK5 can accumulate in the nucleus and regulate processes such as cell proliferation, differentiation, survival, and angiogenesis.

In endothelial cells, shear stress–induced MEK5–ERK5 signaling upregulates KLF2 and KLF4, contributing to vascular homeostasis and anti-inflammatory responses. Biologically, disrupting Mapk7 in mice causes embryonic lethality with cardiovascular defects, indicating an essential role in development. In humans, ERK5 signaling has been implicated in various cancers and in cellular resistance to apoptosis in certain contexts; consequently, ERK5 is investigated as a potential therapeutic target, though targeting it presents challenges due to its roles in normal physiology.

BMK1/ERK5 remains a distinct branch of the MAPK family, with a unique C-terminal regulatory region and context-dependent functions across tissues.