A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 02 2020
04 02 2020
Historique:
received:
12
06
2018
accepted:
10
12
2019
entrez:
6
2
2020
pubmed:
6
2
2020
medline:
22
5
2020
Statut:
epublish
Résumé
IκB kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-κB pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGFβ-activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNFα, Interleukin-1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer.
Identifiants
pubmed: 32019925
doi: 10.1038/s41467-020-14502-x
pii: 10.1038/s41467-020-14502-x
pmc: PMC7000802
doi:
Substances chimiques
Proto-Oncogene Proteins
0
I-kappa B Kinase
EC 2.7.11.10
IKBKB protein, human
EC 2.7.11.10
MAP Kinase Kinase Kinases
EC 2.7.11.25
MAP3K8 protein, human
EC 2.7.11.25
MAP Kinase Kinase 4
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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