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

Jeong Seon Kim, Eun Ju Kim, Hee Sun Kim, Jonathan M. Kurie, Young Ho Ahn

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)337-342
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume491
Issue number2
DOIs
StatePublished - 16 Sep 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • Mitogen-activated protein kinase kinase-4 (MKK4)
  • NFκB non-canonical pathway
  • Senescence
  • c-Jun N-Terminal kinase (JNK)

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