Degradation of IkB is a tightly regulated event that is initiated upon specific phosphorylation by activated IKK. The IKK activity in cells can be purified as a 700 – 900 kDa complex, and has been shown to contain two kinase subunits, IKKa(IKK1) and IKKß (IKK2), and a regulatory subunit NEMO (NF-kB essential modifier) or IKKg (shown in the cartoon below). We are interested in understanding the mechanisms that regulate IKK and the biochemical nature of IKK responsible for transducing signaling from specific NF-kB stimuli.

 

 

NF-kB signaling occurs through either the classical or alternative pathway as depicted at left for CD40 signaling. 

 

In the classical (a.k.a. Canonical) pathway, e.g. upon stimulation by TNFalpha, IKKß is becomes active and phosphorylates IkBs on two N-terminal serine residues. Phosphorylated IkB is recognized by the ubiquitin ligase machinery, leading to its polyubiquitination and degradation by the proteasome.  

 

The alternative (non-canonical) pathway depends only on IKKalpha. The alternative pathway is activated in response to a subset of NF-kB inducers including CD40L (shown), LTß and BAFF, and occurs via NIK-mediated activation of IKKalpha.  Phosphorylation of p100 by IKK leads to ubiquitination and the release of NF-kB complexes, including p52:RelB.