Tyrosine phosphorylation‐dependent activation of NF‐κB

Publisher Website
Google Scholar
Abstract
Phosphorylation of the N-terminal domain of IκB inhibitory subunits induces activation of the transcription factor NF-κB. Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of IκB-α, little is known about the mechanisms that lead to release of active NF-κB in T cells as a consequence of tyrosine phosphorylation of IκB-α[Imbert, V., Rupec, R.A., Livolsi, A., Pahl, H.L., Traenckner, B.M., Mueller-Dieckmann, C., Farahifar, D., Rossi, B., Auberger, P., Baeuerle, P. & Peyron, J.F. (1996) Cell86, 787–798]. The involvement of the tyrosine kinases p56lck and ZAP-70 in this reaction is demonstrated here using specific pharmacological inhibitors and Jurkat mutants unable to express these kinases. Although the inhibitors prevented both pervanadate-induced phosphorylation of IκB-α on Tyr42 and NF-κB activation, we observed that, in p56lck-deficient Jurkat mutants, NF-κB could still associate with IκB-α despite phosphorylation on Tyr42. Furthermore, the SH2 domain of p56lck appeared to be required for pervanadate-induced NF-κB activation but not for Tyr42 phosphorylation. These results show that p56lck and ZAP-70 are key components of the signaling pathway that leads to phosphotyrosine-dependent NF-κB activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF-κB. Finally, we show that H2O2, which stimulates p56lck and ZAP-70 in T cells, is an activator of NF-κB through tyrosine phosphorylation of IκB-α.