A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32019925.
- Also identified by DOI 10.1038/s41467-020-14502-x and PMC identifier 7000802.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- B-Lymphocytes
- Herpesvirus 4, Human
- I-kappa B Kinase
- MAP Kinase Kinase 4
- MAP Kinase Kinase Kinases
- Proto-Oncogene Proteins