MKK6

MKK6, also known as MAP2K6, is a dual-specificity protein kinase that functions as a component of the mitogen-activated protein kinase (MAPK) signaling pathway. It specifically activates members of the p38 MAPK family in response to cellular stress and inflammatory stimuli.

In the MAPK cascade, MKK6 acts as a MAPK kinase (MAPKK) that phosphorylates and activates p38 MAPKs. Activated p38 MAPKs, in turn, regulate a range of cellular processes including gene expression, apoptosis, differentiation, and inflammatory responses by phosphorylating transcription factors and other target proteins. The p38 family comprises several isoforms (p38α, p38β, p38γ, p38δ), which can be differentially activated by MKK6 and related kinases.

MKK6 is activated by phosphorylation on serine and threonine residues within its activation loop by upstream MAPK kinase kinases (MAP3Ks), such as TAK1, ASK1, and MLK family members, as part of cellular responses to stress signals. The active MKK6 then phosphorylates p38 MAPKs on specific residues in their activation loop to promote full kinase activity.

The MAP2K6 gene encodes MKK6 and generates multiple transcript variants through alternative splicing, producing several isoforms that may have distinct tissue distributions or regulatory properties. MKK6 is expressed broadly across tissues and has been implicated in inflammatory and immune responses, stress adaptation, and cancer-related processes. Due to its central role in the p38 pathway, MKK6 is of interest as a potential target for therapies addressing inflammatory diseases and fibrosis, though direct targeting presents challenges given the pathway’s widespread importance.