TY - JOUR
T1 - MKK4 activates non-canonical NFκB signaling by promoting NFκB2-p100 processing
AU - Kim, Jeong Seon
AU - Kim, Eun Ju
AU - Kim, Hee Sun
AU - Kurie, Jonathan M.
AU - Ahn, Young Ho
N1 - Funding Information:
This work was supported under the framework of an international cooperation program managed by the National Research Foundation of Korea (NRF-2016K2A9A1A01950244) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2010-0027945). This study was also supported by the Ewha Womans University scholarship of 2015 (to J. S. Kim).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/9/16
Y1 - 2017/9/16
N2 - 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.
AB - 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.
KW - c-Jun N-Terminal kinase (JNK)
KW - Mitogen-activated protein kinase kinase-4 (MKK4)
KW - NFκB non-canonical pathway
KW - Senescence
UR - http://www.scopus.com/inward/record.url?scp=85025143158&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2017.07.099
DO - 10.1016/j.bbrc.2017.07.099
M3 - Article
C2 - 28733031
AN - SCOPUS:85025143158
SN - 0006-291X
VL - 491
SP - 337
EP - 342
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -
