c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways (JNK/p38 MAPK)

The JNK (c-Jun N-terminal kinase) and p38 MAP kinase signaling pathways are two major branches of the mitogen-activated protein kinase (MAPK) superfamily, collectively known as stress-activated protein kinases (SAPKs) (PubMed: 22252845). These pathways are primarily activated by environmental stresses, such as UV radiation, oxidative stress, and pro-inflammatory cytokines like TNF-alpha and IL-1 (UniProt: P45983, Q16539). Upon activation, these kinases phosphorylate a variety of intracellular targets, including transcription factors like c-Jun and ATF2, which regulate gene expression related to cell death, survival, and the inflammatory response (PubMed: 25035954). In many diseases, including rheumatoid arthritis, neurodegeneration, and certain cancers, these pathways are chronically overactivated, leading to tissue damage and disease progression (PubMed: 20156944). Consequently, they have been extensively explored as therapeutic targets for small-molecule inhibitors. However, clinical development has been challenging due to the high degree of redundancy and the essential roles these kinases play in normal physiology, often resulting in off-target toxicities or lack of sustained efficacy (PubMed: 24453972).

Other names

Stress-activated protein kinase pathwaysSAPK pathwaysMAPK signaling cascadesc-Jun N-terminal kinasep38 mitogen-activated protein kinase

Inhibition of the catalytic activity of JNK and p38 kinases, typically through ATP-competitive binding, which prevents the phosphorylation of downstream substrates such as c-Jun, ATF2, and MAPKAPK2, thereby modulating gene expression and cytokine release (PubMed: 25635915, PubMed: 22252845).