Function
Serine/threonine-protein kinase involved in various cellular processes such as proliferation, differentiation, migration, transformation, and programmed cell death. Extracellular stimuli, such as proinflammatory cytokines or physical stress, activate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases, MAP2K4/MKK4 and MAP2K7/MKK7, phosphorylate and activate MAPK9/JNK2. Subsequently, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1, such as JUN and ATF2, thereby regulating AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, MAPK9/JNK2 inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. It promotes stressed cell apoptosis by phosphorylating key regulatory factors, including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are essential for the polarized differentiation of T-helper cells into Th1 cells. Following T-cell receptor (TCR) stimulation, MAPK9/JNK2 is activated by CARMA1, BCL10, MAP2K7, and MAP3K7/TAK1 to regulate JUN protein levels. MAPK9/JNK2 plays a crucial role in osmotic stress-induced epithelial tight-junction disruption. Upon activation, it promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. MAPK9/JNK2 also participates in neurite growth in spiral ganglion neurons. It phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer, playing a role in the regulation of the circadian clock. Furthermore, MAPK9/JNK2 phosphorylates POU5F1, resulting in the inhibition of POU5F1's transcriptional activity and enhancing its proteosomal degradation. MAPK9 isoforms exhibit distinct binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, while beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which occurs at approximately the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.