Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases.
Phosphorylation of the N-terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF-kappa B. Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome-mediated degradation of I kappa B-alpha, little is known about the mechanisms that lead to release of active NF-kappa B ... in T cells as a consequence of tyrosine phosphorylation of I kappa B-alpha [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) Cell 86, 787--798]. The involvement of the tyrosine kinases p56(lck) 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 I kappa B-alpha on Tyr42 and NF-kappa B activation, we observed that, in p56(lck)-deficient Jurkat mutants, NF-kappa B could still associate with I kappa B-alpha despite phosphorylation on Tyr42. Furthermore, the SH2 domain of p56(lck) appeared to be required for pervanadate-induced NF-kappa B activation but not for Tyr42 phosphorylation. These results show that p56(lck) and ZAP-70 are key components of the signaling pathway that leads to phosphotyrosine-dependent NF-kappa B activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF-kappa B. Finally, we show that H(2)O(2), which stimulates p56(lck) and ZAP-70 in T cells, is an activator of NF-kappa B through tyrosine phosphorylation of I kappa B-alpha.
Mesh Terms:
DNA, DNA-Binding Proteins, Enzyme Activation, Humans, Hydrogen Peroxide, I-kappa B Proteins, Jurkat Cells, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mutation, NF-kappa B, Phosphorylation, Phosphotyrosine, Protein Binding, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Signal Transduction, Stilbenes, T-Lymphocytes, Transcriptional Activation, Vanadates, ZAP-70 Protein-Tyrosine Kinase, src Homology Domains
DNA, DNA-Binding Proteins, Enzyme Activation, Humans, Hydrogen Peroxide, I-kappa B Proteins, Jurkat Cells, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mutation, NF-kappa B, Phosphorylation, Phosphotyrosine, Protein Binding, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Signal Transduction, Stilbenes, T-Lymphocytes, Transcriptional Activation, Vanadates, ZAP-70 Protein-Tyrosine Kinase, src Homology Domains
Eur. J. Biochem.
Date: Mar. 01, 2001
PubMed ID: 11231305
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