c-Jun N-terminal kinase–caspase apoptotic signaling pathway (JNK–caspase pathway)

The c-Jun N-terminal kinase (JNK)–caspase apoptotic signaling pathway is a major stress-activated mitogen-activated protein kinase (MAPK) cascade that plays a central role in determining cell fate in response to environmental stress, DNA damage, and inflammatory cytokines [1.1.1, 1.2.1]. The pathway is initiated by the sequential phosphorylation of upstream kinases, which activate JNK isoforms (JNK1, JNK2, and JNK3) [1.1.2, 1.3.1]. Once activated, JNK translocates to the nucleus to activate transcription factors like c-Jun and p53, or to the mitochondria to modulate Bcl-2 family proteins [1.2.4, 1.3.3]. This modulation ultimately triggers the release of cytochrome c and the activation of the caspase cascade, including Caspase-9 and Caspase-3, to execute programmed cell death [1.3.3, 1.5.1]. Dysregulation of this pathway is a hallmark of various pathologies, including neurodegenerative diseases where excessive JNK activity drives neuronal loss, and cancer, where the pathway can exhibit both tumor-suppressive and oncogenic properties [1.2.2, 1.4.3]. Therapeutic interventions target this pathway using JNK inhibitors to provide neuroprotection or by utilizing chemotherapeutic agents that activate the cascade to eliminate malignant cells [1.4.1, 1.4.4]. However, the complexity of JNK signaling and its involvement in essential physiological processes pose significant challenges for drug development, including risks of systemic toxicity and context-specific effects [1.4.2, 1.5.2].

Other names

JNK/SAPK signaling pathwayStress-activated protein kinase pathwayJNK-mediated apoptotic pathwayc-Jun N-terminal kinase signaling cascade

Modulation of the JNK-caspase cascade, typically through inhibition of JNK kinases to prevent cell death in neurodegeneration or activation of the pathway to induce apoptosis in oncology.