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

Baltimore, 1993), serine phosphorylation triggers a pro-*Inserm Unité 364 teolytic degradation of inhibitory subunits, called I␬B Faculté de Mé decine Pasteur proteins (Brockman et al. The activation of TFs by protein France kinases can directly couple events at cell surface recep-† Institute of Biochemistry tors to nuclear gene expression. STAT factors require Albert-Ludwigs-University only one kinase in their signal transduction pathway Hermann Herder-Str. 7 whereas activation of the nuclear SRF/ets complex in-D-79104, Freiburg volves activation of an entire kinase cascade. Germany NF-␬B/Rel TFs are composed of five distinct DNA-binding subunits, called p50, p52, p65/RelA, c-Rel, and Rel-B (Liou and Baltimore, 1993). The different family Summary members can associate in various homo-or heterodim-ers through a highly conserved N-terminal sequence, The transcription factor NF-␬B regulates genes partic-called the NRD (NF-␬B/rel/Dorsal) (Grimm and Baeuerle, ipating in immune and inflammatory responses. In T 1993) or Rel homology domain. NF-␬B complexes con-lymphocytes, NF-␬B is sequestered in the cytosol by taining the p65 subunit seem to have a pivotal role in the inhibitor I␬B-␣ and released after serine phosphor-the generation of an immune response. NF-␬B, which ylation of I␬B-␣ that regulates its ubiquitin-dependent is activated by antigens, viruses, bacteria, prooxidants, degradation. We report an alternative mechanism of and inflammatory lymphokines, participates in the tran-NF-␬B activation. Stimulation of Jurkat T cells with scriptional initiation of diverse genes whose products the protein tyrosine phosphatase inhibitor and T cell are important in immune and inflammatory responses. activator pervanadate led to NF-␬B activation through Examples are the genes encoding interleukins Ϫ1, Ϫ2, tyrosine phosphorylation but not degradation of I␬B-␣. Ϫ6, and Ϫ8, IL-2 receptor ␣ chain, various adhesion Pervanadate-induced I␬B-␣ phosphorylation and NF-molecules, major histocompatibility class I molecules, ␬B activation required expression of the T cell tyrosine and immunoglobulin ␬ light chain (Baeuerle and Henkel, kinase p56 lck. Reoxygenation of hypoxic cells appeared 1994). as a physiological effector of I␬B-␣ tyrosine phosphor-Inactive NF-␬B is present in the cytosol associated ylation. Tyrosine phosphorylation of I␬B-␣ represents with an inhibitory molecule of the I␬B family (Baeuerle a proteolysis-independent mechanism of NF-␬B acti-and Baltimore, 1988). All six known members of the I␬B vation that directly couples NF-␬B to cellular tyrosine family (I␬B-␣, I␬B-␤, I␬B-␥, Bcl-3, p100, p105, reviewed kinase. in Beg and Baldwin, 1993) contain an ankyrin (ANK) repeat domain that is composed of 5–7 closely adjacent repeats required for both association with NF-␬B and Introduction inhibitory activity (Beg and Baldwin, 1993). Interaction …