SAPKs

Stress-activated protein kinases (SAPKs) are a subset of mitogen-activated protein kinases (MAPKs) that respond to cellular stress and inflammatory signals. In vertebrates, SAPKs primarily comprise the c-Jun N-terminal kinases (JNKs) and the p38 MAP kinases. SAPKs are activated by upstream dual-specificity kinases, known as MKKs; MKK4 and MKK7 activate JNKs, while MKK3 and MKK6 activate p38 proteins. Activation occurs in response to diverse stresses such as ultraviolet radiation, heat shock, reactive oxygen species, osmotic stress, and cytokines, and involves dual phosphorylation of a Thr–X–Tyr motif in the activation loop.

Once activated, SAPKs phosphorylate a wide range of substrates, including transcription factors such as c-Jun and ATF2, as well as other cytosolic and nuclear proteins. This leads to changes in gene expression, modulation of inflammatory responses, control of cell cycle progression, apoptosis, and adaptations in differentiation and development. In addition to transcription factors, SAPKs regulate non-transcriptional processes such as cytoskeletal organization and vesicle trafficking in some contexts.

Regulation of SAPK activity is tightly controlled by phosphatases, particularly the dual-specificity MAP kinase phosphatases (MKPs/DUSPs), which deactivate SAPKs and provide feedback control. Dysregulation of SAPK signaling has been linked to various diseases, including cancer, neurodegenerative and inflammatory disorders, and responses to tissue injury. SAPK pathways are actively studied as potential therapeutic targets, with small-molecule inhibitors used as research tools to dissect signaling networks and, in some cases, as leads for drug development.