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Sci. Signal., 25 May 2010
Vol. 3, Issue 123, p. ra41
[DOI: 10.1126/scisignal.2000778]


Editor's Summary

Activation and Inhibition through IKK{alpha}
Details about the activation and termination of the noncanonical NF-{kappa}B pathway, which is involved in processes such as B cell maturation and bone development, still continue to emerge (see the Perspective by Sun). Central to this pathway is NF-{kappa}B–inducing kinase (NIK), which activates inhibitor of {kappa}B kinase {alpha} (IKK{alpha}). IKK{alpha} phosphorylates an NF-{kappa}B precursor protein called p100, promoting its processing to the mature p52 subunit, which then interacts with the RelB subunit to form the noncanonical NF-{kappa}B complex. Under resting conditions, NIK is constitutively degraded; however, after stimulation of receptors such as B cell–activating factor receptor (BAFF-R) and lymphotoxin β receptor (LTβR), NIK accumulates and initiates noncanonical signaling. Razani et al. observed an increase in the steady-state abundance of NIK in cells from IKK{alpha}-deficient mice and from mice that have a variant NIK protein that is incapable of binding to IKK{alpha}. They identified NIK as a target of IKK{alpha} and showed that phosphorylation of NIK by IKK{alpha} resulted in its destabilization and the inhibition of noncanonical signaling. Further understanding of the regulation of NIK may help in the development of therapies that specifically target noncanonical NF-{kappa}B signaling.

Citation: B. Razani, B. Zarnegar, A. J. Ytterberg, T. Shiba, P. W. Dempsey, C. F. Ware, J. A. Loo, G. Cheng, Negative Feedback in Noncanonical NF-{kappa}B Signaling Modulates NIK Stability Through IKK{alpha}-Mediated Phosphorylation. Sci. Signal. 3, ra41 (2010).

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