Mitogen-activated protein kinase 8

MAPK8 (mitogen-activated protein kinase 8, also known as JNK1) is a serine/threonine-protein kinase that regulates cell proliferation, differentiation, migration, apoptosis, and autophagy through phosphorylation of multiple substrates (UniProt: P45983). The protein functions as a key component of the stress-activated protein kinase (SAP/JNK) signaling pathway, activated by pro-inflammatory cytokines and physical stress. MAPK8 phosphorylates transcription factors including AP-1 components (JUN, ATF2), tumor suppressors (TP53), and proteins regulating cell survival, microtubule dynamics, and circadian rhythm control.

In the nervous system, MAPK8 plays critical roles in neurite elongation and radial migration during brain development through phosphorylation of STMN2 and regulation of microtubule dynamics. The protein also functions in synaptic regulation and responds to oxidative stress by phosphorylating substrates including SIRT6, NLRP3 (inflammasome assembly), and ALKBH5. These activities implicate MAPK8 in both normal neuronal function and stress-response pathways relevant to neurodegeneration.

MAPK8 is significantly down-regulated in post-mortem Alzheimer's disease brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.64 (Chaparral AD proteomics). This reduction may impair cellular stress responses and pro-survival signaling cascades critical for neuronal resilience, potentially contributing to neuronal vulnerability in AD pathogenesis.