Stress-activated protein kinase signaling pathway and Caspase-3 (SAPK/CASP3)

The stress-activated protein kinase (SAPK) pathway, primarily involving the c-Jun N-terminal kinase (JNK) and p38 MAPK subfamilies, is a major signaling route through which cells respond to physical, chemical, and physiological stress [Kyriakis & Avruch, 2012, Physiological Reviews]. Activation of this pathway typically occurs via a cascade of phosphorylation events initiated by MAP kinase kinase kinases (MAP3Ks) and MAP kinase kinases (MAP2Ks) in response to stimuli like UV radiation, oxidative stress, or pro-inflammatory cytokines [Dhanasekaran & Reddy, 2008, Oncogene]. A critical downstream effector of this signaling axis is Caspase-3, the primary executioner protease of the apoptotic program [Porter & Janicke, 1999, Cell Death & Differentiation]. Once activated by upstream initiator caspases or directly influenced by SAPK-mediated mitochondrial signaling, Caspase-3 cleaves essential cellular proteins, leading to the morphological and biochemical hallmarks of apoptosis [Janicke et al., 1998, JBC]. This pathway plays a dual role in human pathology; its overactivation is linked to neuronal loss in neurodegenerative diseases and tissue damage in ischemia, while its evasion is a hallmark of cancer cell survival [Yuan & Yankner, 2000, Nature]. Consequently, the SAPK/Caspase-3 axis is a significant focus for drug development, with inhibitors targeting JNK or p38 being explored for inflammatory and degenerative conditions, and pathway activators being utilized in oncology to induce tumor cell death [Bubici & Papa, 2014, British Journal of Pharmacology].

Other names

JNK/p38 MAPK pathwaySAPK signaling cascadeStress-induced apoptotic pathwayJNK-Caspase 3 axis

Modulation of the signaling cascade through inhibition of upstream stress-activated kinases (JNK/p38) or direct inhibition/activation of the executioner Caspase-3 to regulate programmed cell death [Bubici & Papa, 2014, British Journal of Pharmacology].