Direct Phosphorylation of NF-κB1 p105 by the IκB Kinase Complex on Serine 927 Is Essential for Signal-induced p105 Proteolysis

TrCP-mediated proteolysis of NF-�B1 p105 requires phosphorylation of p105 serines 927

IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell–dependent antigen

The importance of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1(SSAA/SSAA) mice, in which this NF-κB signaling pathway is blocked. Nfkb1(SSAA) mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1(SSAA/SSAA) FM B cells were completely unable to...

Assaying kinase activity of the TPL-2/NF-κB1 p105/ABIN-2 complex using an optimal peptide substrate

The MKK1/2 kinase tumour progression locus 2 (TPL-2) is critical for the production of tumour necrosis factor alpha (TNFα) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small-molecule inhibitors that specifically block TPL-2 signalling in cells, but none of these have...

NF-κB p105 is a target of IκB kinases and controls signal induction of Bcl-3–p50 complexes

The NF-κB precursor p105 has dual functions: cytoplasmic retention of attached NF-κB proteins and generation of p50 by processing. It is poorly understood whether these activities of p105 are responsive to signalling processes that are known to activate NF-κB p50–p65. We propose a model that p105 is inducibly degraded, and that its degradation liberates sequestered NF-κB subunits, including its...

KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth

NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats doma...