Mitogen-activated protein kinase JNK and p38 (JNK/p38 MAPK)

The Mitogen-activated protein kinases JNK (c-Jun N-terminal kinase) and p38 are two major subfamilies of the MAPK superfamily that function as central mediators of the cellular stress response (Kyriakis & Avruch, 2012). These kinases are primarily activated by environmental stressors, such as UV radiation and oxidative stress, as well as pro-inflammatory cytokines like tumor necrosis factor (TNF) and interleukin-1 (IL-1) (UniProt P45983; UniProt Q16539). Upon activation, JNK and p38 phosphorylate a diverse array of substrates, including transcription factors like c-Jun and ATF2, thereby regulating gene expression programs related to apoptosis, inflammation, and cell differentiation (Bubici & Papa, 2014). In clinical contexts, overactivation of these pathways is strongly associated with chronic inflammatory conditions, such as rheumatoid arthritis and Crohn's disease, and neurodegenerative disorders like Alzheimer's disease (Hammouda et al., 2020). While numerous small-molecule inhibitors have been developed to target these kinases—most notably p38 alpha inhibitors like losmapimod—many have failed in clinical trials due to dose-limiting toxicities, including hepatotoxicity and central nervous system effects (Genovese, 2009). Despite these challenges, they remain high-interest targets for precision medicine, particularly in oncology and inflammatory disease management.

Other names

Stress-activated protein kinaseSAPKc-Jun N-terminal kinasep38 mitogen-activated protein kinaseMAPK8/9/10 and MAPK11/12/13/14

Inhibition of kinase activity through ATP-competitive or allosteric binding, preventing the phosphorylation of downstream targets such as c-Jun, ATF2, and HSP27 (Kyriakis & Avruch, 2012).