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

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.

• Authors: Jeong Seon Kim, Eun Ju Kim, Hee-Sun Kim, Jonathan M Kurie, Young-Ho Ahn
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 491 Issue 2 Pg. 337-342 (09 16 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28733031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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