MEK1/2 dual-specificity protein kinases: Structure and regulation

MEK1 and MEK2 are related protein kinases that participate in the RAS–RAF–MEK–ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, cell migration, differentiation, metabolism, and proliferation. Moreover, oncogenic mutations in RAS or B-RAF are responsible for a large proportion of human cancers. MEK1 is activated by phosphorylation of S218 and S222 in its activation segment as catalyzed by RAF kinases in an intricate process that involves a KSR scaffold. Besides functioning as a scaffold, the kinase activity of KSR is also required for MEK activation. MEK1 regulation is unusual in that S212 phosphorylation in its activation segment is inhibitory. Moreover, active ERK catalyzes a feedback inhibitory phosphorylation of MEK1 T292 that serves to downregulate the pathway.

► MEK1 is activated by phosphorylation of S218 and S222 in its activation segment.
► MEK1 activation requires KSR, which functions as a scaffold and a protein kinase.
► S212 phosphorylation in the MEK1 activation segment is inhibitory.
► MEK1 and MEK2 contain a catalytic and a regulatory spine.