Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway.
In mammals, the canonical nuclear factor kappaB (NF-kappaB) signaling pathway activated in response to infections is based on degradation of IkappaB inhibitors. This pathway depends on the IkappaB kinase (IKK), which contains two catalytic subunits, IKKalpha and IKKbeta. IKKbeta is essential for inducible IkappaB phosphorylation and degradation, whereas IKKalpha is not. Here we show that IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappaB2 (p100) precursor. IKKalpha preferentially phosphorylates NF-kappaB2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK). IKKalpha is therefore a pivotal component of a second NF-kappaB activation pathway based on regulated NF-kappaB2 processing rather than IkappaB degradation.
Senftleben
U
U
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cao
Y
Y
Xiao
G
G
Greten
F R
FR
Krähn
G
G
Bonizzi
G
G
Chen
Y
Y
Hu
Y
Y
Fong
A
A
Sun
S C
SC
Karin
M
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation; D018858:Germinal Center; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007072:Immunoglobulin D / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008221:Lymphoid Tissue / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007072:Immunoglobulin D; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000097782:NF-kappaB-Inducing Kinase; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse