MAPKK

MAPKK, short for mitogen-activated protein kinase kinase, is a dual-specificity protein kinase that sits in the MAPK signaling cascade. It activates MAP kinases by phosphorylating them on both a threonine and a tyrosine residue within their activation loop. MAPKKs are themselves activated by upstream MAPKKKs through phosphorylation on serine residues in their activation segment. In mammals, the best-characterized MAPKKs are MEK1 and MEK2 (MAPKK1/2) and the related group MKK3–MKK7 (MKKs 3–7).

Activated MAPKKs target the principal MAPKs: ERKs, JNKs, and p38. MEK1/2 phosphorylate ERK1/2; MKK4/7 activate JNKs (and can activate some p38 signaling); MKK3/6 activate p38. Through these interactions, MAPKKs relay signals from growth factors, cytokines, and stress to control gene expression, cell cycle progression, differentiation, and survival. Signaling specificity is shaped by scaffold proteins and feedback regulation that modulate pathway strength and duration.

Dysregulation of MAPKK signaling is linked to disease, notably cancer, inflammatory disorders, and developmental syndromes. Therapeutically, MEK inhibitors such as trametinib, selumetinib, cobimetinib, and binimetinib are used to treat cancers with aberrant MAPK signaling, especially BRAF-mutant tumors. Resistance mechanisms often involve reactivation of the MAPK pathway or compensatory signaling; side effects can include rash, diarrhea, edema, and cardiotoxicity.

MAPKKs are conserved across eukaryotes, including plants, where MAPK cascades govern responses to biotic and abiotic stress and developmental processes. The core cascade remains MAPKKK → MAPKK → MAPK, with specificity refined by docking interactions and scaffolds.