MEKs

MEKs, short for mitogen-activated protein kinase kinases, are dual-specificity serine/threonine and tyrosine kinases that activate the ERK1/2 proteins by phosphorylation. In humans they are represented by two closely related paralogs, MEK1 (MAP2K1) and MEK2 (MAP2K2). They function downstream of the Ras-Raf signaling cascade as a central part of the MAPK/ERK pathway, transmitting mitogenic and survival signals to regulate gene expression.

MEK1 and MEK2 are activated by phosphorylation through upstream Raf kinases in response to growth factors, cytokines, and other stimuli. Once activated, MEK1/2 phosphorylate ERK1/2 on a conserved TEY motif, enabling ERK to dimerize, translocate to the nucleus, and modulate transcription factors and other substrates. MEK activity is modulated by multiple feedback mechanisms, including ERK-mediated feedback, and by phosphatases and other regulatory proteins that influence localization and duration of signaling.

Biological roles of MEK1/2 include control of cell proliferation, differentiation, and development. Dysregulation of MEK-ERK signaling is implicated in various cancers and developmental disorders known as RASopathies. Because of their central position in a pro-proliferative signaling cascade, MEKs are important targets in precision oncology.

Therapeutically, MEK inhibitors such as trametinib, cobimetinib, selumetinib, and binimetinib are used to treat cancers with aberrant MAPK signaling, most notably BRAF-mutant melanoma (often in combination with RAF inhibitors) and certain non-small cell lung cancers. Side effects can include rash, diarrhea, edema, and cardiovascular effects. Resistance to MEK inhibitors can arise via pathway reactivation or activation of parallel signaling routes, prompting ongoing research into combination strategies and alternative targets.