Dual specificity mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)

Dual specificity mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) are essential components of the RAS/RAF/MEK/ERK signaling pathway, which plays a pivotal role in regulating cell growth, proliferation, and survival (UniProt: Q02750, P36507). These enzymes are unique dual-specificity kinases that activate their only known physiological substrates, ERK1 and ERK2, by phosphorylating both threonine and tyrosine residues within a conserved Thr-Glu-Tyr motif (StatPearls: MAPK Pathway). Hyperactivation of this pathway, frequently caused by upstream mutations in BRAF or RAS, is a primary driver in various malignancies, including cutaneous melanoma and colorectal cancer (NCI: MEK Inhibitors). Consequently, MEK1/2 have become significant therapeutic targets, with several small-molecule inhibitors approved for use, often in combination with BRAF inhibitors to overcome resistance. Most clinical MEK inhibitors function through an allosteric mechanism, binding to a pocket adjacent to the ATP-binding site to lock the enzyme in an inactive conformation (PubMed: 24345360). Beyond oncology, germline mutations in the genes encoding MEK1/2 are associated with RASopathies, a group of developmental syndromes characterized by cardiac defects, facial dysmorphism, and cognitive impairment (NIH: Genetics Home Reference).

Other names

MAP2K1MAP2K2MEK1MEK2MKK1MKK2Mitogen-activated protein kinase kinase 1Mitogen-activated protein kinase kinase 2ERK activator kinase 1ERK activator kinase 2

Allosteric inhibition of MEK1 and MEK2, preventing the phosphorylation and subsequent activation of downstream ERK1 and ERK2 (PubMed: 30215164).