ERK5

ERK5, also known as MAPK7 or BMK1, is a member of the mitogen-activated protein kinase (MAPK) family. It is activated by the upstream kinase MEK5 and represents a distinct MAPK signaling node due to its unusually large C-terminal tail and its specific regulatory inputs. ERK5 participates in responses to growth factors as well as cellular stress.

ERK5 is encoded by the MAPK7 gene and is commonly referred to as BMK1 (big mitogen-activated protein kinase 1). The protein contains a conserved N-terminal catalytic kinase domain and a long C-terminal tail that includes a transcriptional activation region and nuclear localization signals. Activation occurs at the TEY motif in the activation loop, with Thr218 and Tyr220 phosphorylation.

Activation of ERK5 requires MEK5 (MAP2K5), which is in turn regulated by MEKK family kinases (MEKK2/3) and other inputs. Stimuli include vascular and growth signals such as VEGF and EGF, osmotic stress, shear stress in endothelial cells, and inflammatory cues. Once activated, ERK5 can phosphorylate cytoplasmic substrates and translocate to the nucleus.

In the nucleus, ERK5 influences gene expression by modulating transcription factors such as MEF2 family members and Sap1/Net. It also has kinase-independent effects through the C-terminal tail. Functionally, ERK5 regulates cell proliferation, differentiation, survival, angiogenesis, and neural and cardiovascular development.

Biologically and clinically, ERK5 signaling is studied for its roles in cancer and cardiovascular disease. Specific ERK5 inhibitors have been developed (for example, MEK5 inhibitors and ERK5 selective inhibitors), but selectivity remains a concern in some compounds. The ERK5 pathway is essential for vascular development in mice; knockout models display embryonic lethality due to defects in angiogenesis.