MEK5

MEK5 (MAP2K5) is a dual-specificity MAPK kinase that functions as the direct upstream activator of ERK5/MAPK7, forming the core of the MEK5-ERK5 signaling module within the mitogen-activated protein kinase network^[1][2]. Mechanistically, MEK5 is activated downstream of MEKK2 and MEKK3, and transmits signals that regulate cell survival, proliferation, differentiation, migration, and stress-responsive transcriptional programs through ERK5 activation^[2][3]. The pathway is unusual among MAPK cascades because it responds to both mitogenic and stress-related stimuli, including cytokines, oxidative stress, osmotic stress, and fluid shear stress, linking environmental sensing to adaptive cellular responses^[1]. In physiological systems, MEK5-ERK5 signaling has a prominent role in endothelial mechanotransduction and contributes to the maintenance of tissue integrity in mechanically stressed tissues such as bone, cartilage, and muscle^[1]. In disease models, aberrant activation of the pathway has been associated with tumor cell survival, proliferation, therapeutic resistance, and adaptive signaling during targeted cancer treatment^[1][4]. Compared with the closely related MEK1/2-ERK1/2 pathway, MEK5 exhibits distinct signaling specificity because MEK5 activates ERK5 but not ERK1/2, whereas MEK1/2 do not activate ERK5, supporting the functional separation of these parallel MAPK modules^[4]. For experimental applications, selective MEK5 inhibitors such as BIX02189 are widely used to interrogate MEK5-ERK5 pathway function in cellular and disease models^[4][5].