Dual specificity mitogen-activated protein kinase kinase 1 (MEK1) (MEK1)

Dual specificity mitogen-activated protein kinase kinase 1 (MEK1), encoded by the MAP2K1 gene, is a central component of the RAS/RAF/MEK/ERK signaling pathway [1]. It functions as a dual-specificity kinase, meaning it can phosphorylate both tyrosine and serine/threonine residues on its only known physiological substrates, ERK1 and ERK2 [1, 2]. MEK1 is activated through phosphorylation by upstream RAF kinases (ARAF, BRAF, or CRAF), which are themselves activated by RAS proteins in response to extracellular growth signals [2]. This pathway is frequently hyperactivated in human cancers, particularly through BRAF V600E or RAS mutations, leading to uncontrolled cell proliferation and survival [3]. Consequently, MEK1 is a major therapeutic target in oncology, with several FDA-approved allosteric inhibitors like trametinib and cobimetinib used to treat BRAF-mutant melanoma and other malignancies [3, 4]. Beyond cancer, germline mutations in MEK1 are associated with RASopathies, such as cardiofaciocutaneous syndrome, which involve developmental delays and cardiac defects [1, 2].

Other names

MAP2K1MAP kinase kinase 1MKK1PRKMK1ERK activator kinase 1

Allosteric inhibition of MEK1 and MEK2 activity, preventing their activation by upstream RAF kinases and their subsequent phosphorylation of downstream ERK1/2 kinases.