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

Biochem Biophys Res Commun. 2017 Sep 16;491(2):337-342. doi: 10.1016/j.bbrc.2017.07.099. Epub 2017 Jul 18.

Abstract

The NFκB family of transcription factors is crucial for innate or adaptive immunity, inflammation, and diseases including cancer. The two NFκB signaling pathways (canonical and non-canonical) differ from each other in extracellular signals, membrane receptors, signaling adaptors, and dimer subunits. The p52 (NFκB2) subunit, which participates in the non-canonical pathway, is generated by ubiquitin-mediated processing of the p100 precursor. Here, we found that NFκB2 processing and activation were mediated by mitogen-activated protein kinase kinase-4 (MKK4) and its substrate c-Jun N-terminal kinase (JNK). In MKK4-null mouse embryonic fibroblasts (MEFs), serum- and lymphotoxin β receptor (LTβR) antibody-induced processing of p100 and nuclear translocation of p52 were found to be defective. Serum and LTβR 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 NFκB pathway, was observed more frequently in MKK4-null MEFs than in wildtype cells. These results suggest that the MKK4/JNK-dependent pathway regulates NFκB2 processing/activation and, through this mechanism, MKK4 and NFκB2 control cellular growth and senescence.

Keywords: Mitogen-activated protein kinase kinase-4 (MKK4); NFκB non-canonical pathway; Senescence; c-Jun N-Terminal kinase (JNK).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • Bronchi / cytology
  • Bronchi / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Humans
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / metabolism
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Kinase 4 / genetics*
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • NF-kappa B p52 Subunit / genetics*
  • NF-kappa B p52 Subunit / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction

Substances

  • Anthracenes
  • LTBR protein, human
  • Lymphotoxin beta Receptor
  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • Protein Kinase Inhibitors
  • pyrazolanthrone
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human