Stress-activated protein kinases (SAPK) (SAPK)

The p38 and JNK (c-Jun N-terminal kinase) pathways represent two major branches of the mitogen-activated protein kinase (MAPK) signaling cascade, collectively known as stress-activated protein kinases (SAPKs) (StatPearls, 2023). These kinases are primarily activated by environmental stresses, such as UV radiation, heat shock, and osmotic stress, as well as by pro-inflammatory cytokines like TNF-alpha and IL-1 (UniProt, 2024). Upon activation, p38 and JNK phosphorylate a variety of intracellular targets, including transcription factors like c-Jun and ATF2 that regulate genes involved in inflammation, cell proliferation, and apoptosis (PubMed, PMID: 16113111). In disease states, chronic activation of these pathways is linked to the pathogenesis of rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative conditions like Alzheimer's disease (PubMed, PMID: 16443304). Therapeutic strategies have focused on developing small-molecule inhibitors to block these kinases; however, clinical success has been limited by off-target toxicities and the complex redundancy of MAPK signaling (PubMed, PMID: 29441148). Despite these challenges, they remain significant targets for treating chronic inflammatory and fibroproliferative disorders.

Other names

p38 mitogen-activated protein kinasesc-Jun N-terminal kinasesJNKp38 MAPKStress-activated protein kinasesMAPK pathway kinases p38 and JNK

Competitive inhibition of the ATP-binding site or allosteric inhibition of p38 and JNK kinases, preventing the phosphorylation of downstream substrates such as transcription factors (e.g., c-Jun, ATF2) and pro-inflammatory cytokines (PubMed, PMID: 16113111; StatPearls, 2023).