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

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12 Scopus citations


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
Issue number2
StatePublished - 16 Sep 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.


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


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