JNKs

JNKs, or c-Jun N-terminal kinases, are a subgroup of the mitogen-activated protein kinase (MAPK) family known as stress-activated protein kinases (SAPK). In mammals, there are three JNK genes: MAPK8 (JNK1), MAPK9 (JNK2), and MAPK10 (JNK3). Each gene can generate multiple isoforms through alternative splicing, commonly resulting in p46 and p54 protein forms, with tissue distribution differences: JNK1 and JNK2 are widely expressed, while JNK3 is enriched in the brain, heart, and testis.

JNKs are activated by various stress-related signals, including cytokines, UV irradiation, reactive oxygen species, and endoplasmic reticulum stress. Activation occurs via dual phosphorylation on threonine and tyrosine residues in the activation loop (Thr183 and Tyr185) by upstream dual-specificity kinases, notably MKK4 and MKK7. Once activated, JNKs phosphorylate substrates such as transcription factors c-Jun, ATF2, and JunD, as well as non-transcriptional targets like Bcl-2 family proteins and p53, influencing gene expression, apoptosis, and differentiation.

Functional roles and clinical relevance: JNK signaling participates in development, inflammation, metabolism, and stress responses. JNK activity is linked to neuronal apoptosis in ischemia and in neurodegenerative diseases, with JNK3 playing a prominent neuronal role. In insulin resistance and obesity, JNK signaling modulates inflammatory pathways. Cross-talk exists with other MAPK pathways and NF-κB; scaffolding proteins such as JIP1/2 and POSH organize signaling complexes.

Pharmacology and disease: Inhibitors like SP600125 are used in research to block JNK activity, but they lack high specificity. Abnormal JNK signaling is implicated in cancer, neurodegeneration, metabolic disease, and inflammatory conditions, prompting ongoing therapeutic investigations.