JNK3

c-Jun N-terminal kinase 3 (JNK3) is a stress-activated protein kinase predominantly expressed in neurons, pancreatic β-cells, and cardiac tissue^[1][2]. Mechanistically, JNK3 modulates transcriptional programs by phosphorylating c-Jun and regulating downstream factors such as Forkhead BoxO3A (FoxO3A) and Insulin Receptor Substrate 2 (IRS2), thereby maintaining cell survival under stress conditions^[3][2]. In neuronal models, JNK3 contributes to axonal injury signaling and apoptosis, with combined JNK2/3 deficiency markedly reducing retinal ganglion cell death, highlighting its role in neurodegenerative processes^[4][5]. Compared with ubiquitously expressed JNK1 and JNK2, JNK3 demonstrates nuclear localization in β-cells and isoform-specific protective effects against cytokine-induced apoptosis^[2][3]. In the hypothalamus, JNK3 influences energy homeostasis by counteracting JNK1-mediated feeding and weight gain, illustrating its unique physiological role among isoforms^[6][7]. JNK3 activation is scaffold-dependent, particularly via arrestin-3, enabling specific phosphorylation by upstream MKK4/7 kinases and contributing to selective signal propagation^[8]. Structurally selective inhibitors targeting JNK2/3 demonstrate that hydrophobic pocket residues, including L144 in JNK3, determine isoform-specific binding, providing tools for experimental modulation of neuroprotection and β-cell survival^[9][10]. Overall, JNK3 serves as a critical mediator of stress responses, with distinct subcellular localization and signaling effects compared with JNK1/2, making it a valuable target for studying neurodegeneration and metabolic regulation.