MAP2K1MAP2K2

MAP2K1 and MAP2K2 are human genes that encode the dual-specificity kinases MEK1 and MEK2, respectively. In the MAPK/ERK signaling cascade, MEK1/MEK2 act as central regulators that relay signals from upstream RAF kinases to ERK1/2, controlling cellular processes such as proliferation, differentiation, and survival.

Activation and function: Upstream signals such as growth factors activate receptor tyrosine kinases and RAS, leading to RAF activation. RAF kinases phosphorylate and activate MEK1 and MEK2, which in turn phosphorylate ERK1 and ERK2 on specific residues in their activation loop. Activated ERK1/2 then translocate to the nucleus where they regulate gene expression and other cellular targets. MEK1 and MEK2 have overlapping but not identical roles and can be differentially regulated by scaffolding proteins and feedback mechanisms.

Clinical and biological relevance: Mutations in MAP2K1 or MAP2K2 have been identified in various cancers and in developmental disorders characterized by dysregulated MAPK signaling, including cardio-facio-cutaneous–like syndromes and Noonan spectrum conditions. Because MEK1/MEK2 lie downstream of RAS and RAF, they are attractive therapeutic targets. MEK inhibitors such as trametinib, cobimetinib, and binimetinib are used clinically to block MAPK signaling in certain tumors, particularly those with upstream pathway activation or resistance to other inhibitors. Combination strategies with RAF inhibitors have shown effectiveness in some BRAF-mutant cancers, though ongoing management of resistance and side effects remains an area of active research.

Regulation and interactions: MEK1/MEK2 are regulated by phosphorylation, scaffolding interactions (notably with KSR proteins), and phosphatases that modulate downstream ERK activity. They principally phosphorylate ERK1/2, linking extracellular signals to transcriptional programs.