Abstract
Author SummaryThe germinal center kinase family member TNIK was discovered in a yeast-two-hybrid screen for interaction partners of the adapter proteins TRAF2 and Nck, and here we show it is one of the missing molecular players in two key signaling pathways in B-lymphocytes. We found that TNIK is crucial for the activities of the CD40 receptor on Bcells and its viral mimic, the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). EBV is a human DNA tumor virus that is associated with various malignancies. It targets and transforms B-cells by hijacking the cellular signaling machinery via its oncogene LMP1. In normal Bcell physiology, the CD40 receptor is central to the immune response by mediating B-cell activation and proliferation. TNIK turns out to be an organizer of the LMP1- and CD40-induced signaling complexes by interacting with the TRAF6 adapter protein, well known for its role in linking distinct signaling pathways. Through this mechanism the two receptors depend on TNIK to activate the canonical NF-κB and JNK signal transduction pathways, which are important for the physiological activation of B-cells (a process that enables antibody production), as well as for their transformation into tumor cells. TNIK thus constitutes a key player in the transmission of physiological and pathological signals in human B-cells that might serve as a future therapeutic target against B-cell malignancies.
Highlights
tumor necrosis factor-receptor-associated factor 2 (TRAF2)- and Nck-interacting kinase (TNIK) was discovered in a yeast-two-hybrid screen for interaction partners of the adapter proteins TRAF2 and Nck [1]
The outgrowth of lymphoblastoid cell line (LCL)-tobacco etch virus (TEV) cells further proved that HA-latent membrane protein 1 (LMP1)-liTEV-CT was fully functional because an intact LMP1 is mandatory for B-cell transformation by Epstein-Barr virus (EBV) [11]
In this study we have identified and characterized the germinal center kinase family member TRAF2- and Nck-interacting kinase (TNIK) as a novel component of the TRAF6/TGFb-receptor-associated kinase 1 (TAK1)/TAK1-binding protein 2 (TAB2)/IKKb complex
Summary
TNIK was discovered in a yeast-two-hybrid screen for interaction partners of the adapter proteins TRAF2 and Nck [1]. The serine/threonine kinase TNIK is a member of the germinal center kinase (GCK) family, which belongs to the Ste group of kinases [2]. GCKs share high sequence homology in their N-terminal kinase and C-terminal germinal center kinase homology (GCKH) domains, while the intermediate domain is less conserved [2]. Current knowledge about the molecular and biological functions of TNIK is very limited. TNIK overexpression modulates the actin cytoskeleton and activates the JNK pathway, which is induced through the GCKH domain by a yet undefined mechanism [1,3]. The molecular function of TNIK’s interaction with TRAF molecules is unclear.
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