Signaling Molecules of the NF-κB Pathway Shuttle Constitutively between Cytoplasm and Nucleus*

By A. Birbach, Peter Gold, B. Binder, E. Hofer, R. de Martin, Johannes A. Schmid. Journal of Biological Chemistry, 2002

271 citations recorded by the source corpus.

We aimed to investigate the dynamics of the NF-κB signaling pathway in living cells using GFP variants of p65-NF-κB, IκBα, tumor necrosis factor-receptor associated factor 2 (TRAF2), the NF-κB inducing kinase (NIK) and IκB kinases (IKK1 and IKK2). Detailed kinetic analysis of constitutive nucleocytoplasmic shuttling processes revealed that IκBα enters the nucleus faster than p65. Examination of signaling molecules upstream of NF-κB and IκBα revealed a predominant cytoplasmic localization at steady state. However, after addition of leptomycin B, NIK rapidly accumulated in the nucleus, whereas we could not detect any significant effect on TRAF2 or IKK2. Using various truncation mutants of NIK, we identified a functional nuclear export signal within the COOH-terminal region 795–805, which counteracts the inherent NLS at amino acids 143–149. Prolonged incubation in the presence of LMB also leads to nuclear accumulation of IKK1, which was dependent on a lysine residue at position 44, which is also essential for kinase activity. Investigation of endogenous protein levels by immunofluorescence staining and Western blots verified the results obtained with GFP chimeras. We conclude that NF-κB·IκB complexes and the upstream signaling kinases NIK and IKK1 shuttle between cytoplasm and nucleus of nonactivated cells and that this process leads to a basal transcriptional activity of NF-κB.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/c1e76ad6d806c5406a92e380269b3d2354d84582

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Citations in the corpus

Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. (2007, background): “blocks RANTES expression in response to U-STAT3 In the absence of an activating signal, the steady-state equilibrium for NF B localization is toward the cytosol, as a result of interaction with I B (Birbach et al. 2002).”
The complexity of NF-κB signaling in inflammation and cancer (2013, background): “Nevertheless, shuttling between cytosol and nucleus does occur [12,13], which might be a basis for a low basal transcriptional activity of NF-κB given that the IκB/NF-κB complex is subject to dissociation and re-association processes.”
Neutrophils and acute lung injury (2003, background): “Although I B molecules initially were thought to reside only in the cytoplasm, recent evidence shows that they shuttle in and out of the nucleus and have an important role in regulating the presence and activity of NF- B dimers in the nucleus as well as the cytoplasm (24).”