MKKs

MKKs, or MAP kinase kinases, are a family of dual-specificity protein kinases that activate MAPKs by phosphorylating them on both threonine and tyrosine residues. They lie downstream of MAPKKKs in the MAPK signaling cascades and are essential for transducing extracellular signals into cellular responses.

In mammals, three main groups correspond to different MAPK pathways: MEK1/2 (MAP2K1/2) activate ERK1/2; MKK4/7 activate JNK and, in some contexts, p38; MKK3/6 activate p38. They themselves are phosphorylated on serine/threonine residues by MAPKKKs such as RAF kinases (ERK pathway) or TAK1/ASK1 (JNK/p38 pathways). Activated MKKs then phosphorylate MAPKs in the activation loop at threonine and tyrosine residues (TEY motif for ERK, TGY motif for JNK/p38). They are regulated by scaffolds, subcellular localization, and feedback loops that shape the strength and duration of signaling.

Human genes encoding MKKs include MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K3 (MKK3), MAP2K4 (MKK4), MAP2K5 (MKK5), MAP2K6 (MKK6), and MAP2K7 (MKK7). The MEK-ERK axis influences cell proliferation and differentiation, while the JNK and p38 axes respond to cellular stress, inflammation, and apoptosis. Dysregulation of MKK signaling is associated with cancer, inflammatory diseases, and developmental disorders. Pharmacological inhibitors targeting MEK1/2 are used clinically in certain cancers and other conditions.

MKKs are conserved across eukaryotes and central to integrating environmental cues into appropriate cellular programs, with ongoing research into their precise regulatory mechanisms and therapeutic potential.