title: The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro.
abstract: Nuclear factor kappaB (NF-kappaB) is a eukaryotic member of the Rel family of transcription factors whose biological activity is post-translationally regulated by its assembly with various ankyrin-rich cytoplasmic inhibitors, including IkappaBalpha. Expression of NF-kappaB in the nucleus occurs after signal-induced phosphorylation, ubiquitination, and proteasome-mediated degradation of IkappaBalpha. The induced proteolysis of IkappaBalpha unmasks the nuclear localization signal within NF-kappaB, allowing its rapid migration into the nucleus, where it activates the transcription of many target genes. At present, the identity of the IkappaBalpha kinase(s) that triggers the first step in IkappaBalpha degradation remains unknown. We have investigated the potential function of the 90-kDa ribosomal S6 kinase, or pp90(rsk), as a signal-inducible IkappaBalpha kinase. pp90(rsk) lies downstream of mitogen-activated protein (MAP) kinase in the well characterized Ras-Raf-MEK-MAP kinase pathway that is induced by various growth factors and phorbol ester. We now show that pp90(rsk), but not pp70(S6K) or MAP kinase, phosphorylates the regulatory N terminus of IkappaBalpha principally on serine 32 and triggers effective IkappaBalpha degradation in vitro. When co-expressed in vivo in COS cells, IkappaBalpha and pp90(rsk) readily assemble into a complex that is immunoprecipitated with antibodies specific for either partner. While phorbol 12-myristate 13-acetate produced rapid activation of pp90(rsk), in vivo, other potent NF-kappaB inducers, including tumor necrosis factor alpha and the Tax transactivator of human T-cell lymphotrophic virus, type I, failed to activate pp90(rsk). These data suggest that more than a single IkappaBalpha kinase exists within the cell and that these IkappaBalpha kinases are differentially activated by different NF-kappaB inducers.
authors.affiliation: University of Colorado Health Sciences Center, Department of Pharmacology, School of Medicine, Denver, Colorado 80262, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ghoda
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: W C
authors.initials: WC
authors.lastname: Greene
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D016356:Gene Products, tax / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D019893:Ribosomal Protein S6 Kinases; D013601:T-Lymphocytes; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D013755:Tetradecanoylphorbol Acetate