Mitogen-activated protein kinase kinase kinase 12 (MAP3K12)

Mitogen-activated protein kinase kinase kinase 12 (MAP3K12), also known as Dual leucine zipper kinase (DLK), is a serine/threonine-protein kinase predominantly expressed in neurons. It is a critical upstream regulator of kinase cascades that mediate responses to cellular stress, axonal injury, and neuronal development. MAP3K12 activates the MAPK/JNK pathway by phosphorylating and activating MKK7, leading to downstream activation of c-Jun and other transcription factors, ultimately regulating processes such as axon growth, neuronal migration, apoptosis, and axonal degeneration. DLK plays key roles in nervous system development, injury responses, neurodegeneration, and regeneration, and is considered an emerging therapeutic target for neurodegenerative disorders. Selective inhibition of MAP3K12/DLK is neuroprotective in experimental models, but safety concerns remain due to its roles in normal neuronal function and development.

Other names

Dual leucine zipper kinase (DLK)MEKK12MUKZPKZPKP1Leucine-zipper protein kinaseMAPK-upstream kinaseMixed lineage kinasedual leucine zipper bearing kinaseprotein kinase MUK

Inhibition of MAP3K12/DLK reduces phosphorylation of MKK7 and JNK, blocking pro-apoptotic and degenerative signaling in neurons, thereby providing neuroprotection