Tyrosine Phosphorylation of IκB-α Activates NF-κB without Proteolytic Degradation of IκB-α

AbstractThe transcription factor NF-κB regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-κB is sequestered in the cytosol by the inhibitor IκB-α and released after serine phosphorylation of IκB-α that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-κB activation. Stimulation of Jurkat T cells with the protein tyrosine phosphatase inhibitor and T cell activator pervanadate led to NF-κB activation through tyrosine phosphorylation but not degradation of IκB-α. Pervanadate-induced IκB-α phosphorylation and NF-κB activation required expression of the T cell tyrosine kinase p56lck. Reoxygenation of hypoxic cells appeared as a physiological effector of IκB-α tyrosine phosphorylation. Tyrosine phosphorylation of IκB-α represents a proteolysis-independent mechanism of NF-κB activation that directly couples NF-κB to cellular tyrosine kinase