MKK4 activates non-canonical NFκB signaling by promoting NFκB2-p100 processing

The NF kappa B family of transcription factors is crucial for innate or adaptive immunity, inflammation, and diseases including cancer. The two NF kappa B signaling pathways (canonical and non-canonical) differ from each other in extracellular signals, membrane receptors, signaling adaptors, and dimer subunits. The p52 (NF kappa B2) subunit, which participates in the non-canonical pathway, is generated by ubiquitin-mediated processing of the p100 precursor. Here, we found that NF kappa B2 processing and activation were mediated by mitogen-activated protein kinase kinase-4 (MKK4) and its substrate c-Jun N-terminal kinase (INK). In MKK4-null mouse embryonic fibroblasts (MEFs), serum- and lymphotoxin (3 receptor (LT(312) antibody induced processing of p100 and nuclear translocation of p52 were found to be defective. Serum and LT beta R. antibody activated the MKK4-JNK signaling pathway, and SP600125, a JNK inhibitor, blocked p100 processing. Cellular senescence, one of the responses regulated by the non-canonical NF kappa B pathway, was observed more frequently in MKK4-null MEFs than in wildtype cells. These results suggest that the MKK4/JNK-dependent pathway regulates NF kappa B2 processing/activation and, through this mechanism, MKK4 and NF kappa B2 control cellular growth and senescence. (C) 2017 Elsevier Inc. All rights reserved.