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

The JNK/MAPK stress kinase pathways, primarily comprising the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) cascades, are critical signal transduction modules that respond to environmental and physiological stressors. These pathways, often collectively referred to as stress-activated protein kinase (SAPK) pathways, regulate a wide array of cellular processes including apoptosis, inflammation, cell proliferation, and differentiation. In disease states, dysregulated JNK and p38 signaling are implicated in the pathogenesis of various cancers, chronic inflammatory conditions like rheumatoid arthritis and COPD, and neurodegenerative disorders such as Alzheimer's disease. Therapeutic targeting of these pathways involves small-molecule inhibitors designed to block the kinase activity of specific isoforms, such as JNK1/2/3 or p38 alpha/beta/gamma/delta. These inhibitors typically act by competing with ATP for the kinase active site, thereby preventing the phosphorylation of downstream targets. While several inhibitors have shown promise in preclinical and early clinical trials, challenges such as systemic toxicity, particularly hepatotoxicity and cardiotoxicity, as well as the development of tachyphylaxis, have hindered their clinical advancement. Furthermore, the dual role of these pathways as both tumor suppressors and promoters depending on the cellular context adds a layer of complexity to drug development.

Other names

Stress-activated protein kinase (SAPK) pathwaysJNK/p38 MAPK signalingStress-activated MAPK pathwaysJNK/MAPK stress kinase pathways

Inhibition of the catalytic activity of JNK and/or p38 MAPK enzymes, preventing the phosphorylation of downstream substrates such as c-Jun, ATF2, and various heat shock proteins, thereby modulating the cellular response to stress and inflammatory cytokines.