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

The c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways are two major signaling cascades collectively known as the stress-activated protein kinase (SAPK) pathways (Kyriakis & Avruch, 2012, Physiol Rev). These pathways are activated by a wide range of environmental stresses, including UV radiation, oxidative stress, and pro-inflammatory cytokines like TNF-alpha and IL-1beta (Wagner & Nebreda, 2009, Nat Rev Cancer). Upon activation, these kinases phosphorylate various intracellular targets, including transcription factors such as c-Jun, ATF2, and p53, thereby regulating gene expression programs related to cell death, survival, and the inflammatory response (Arthur & Ley, 2013, Nat Rev Immunol). In many chronic diseases, such as rheumatoid arthritis and neurodegenerative disorders, these pathways are overactive, leading to persistent inflammation and tissue damage (Hammaker & Firestein, 2010, Ann Rheum Dis). Consequently, they have been extensively studied as therapeutic targets, with numerous small-molecule inhibitors developed to block their activity (Genovese, 2009, Arthritis Rheum). Most of these inhibitors target the ATP-binding site of the kinases to prevent the phosphorylation of downstream effectors. Despite their potential, clinical success has been limited by significant safety concerns, including hepatotoxicity and central nervous system side effects. Furthermore, the high degree of crosstalk and redundancy within the MAPK network often complicates the therapeutic outcome of single-pathway inhibition.

Other names

Stress-activated protein kinase pathwaysSAPK pathwaysJNK/p38 signaling cascadesStress-responsive MAPK pathways

Small molecule inhibition of kinase activity, typically through ATP-competitive binding, preventing the phosphorylation of downstream transcription factors and effector proteins.