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Sci. Signal., 25 May 2010
Vol. 3, Issue 123, p. ra41
Activation and Inhibition through IKK
Details about the activation and termination of the noncanonical NF-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-B–inducing kinase (NIK), which activates inhibitor of B kinase (IKK). IKK phosphorylates an NF-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-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-deficient mice and from mice that have a variant NIK protein that is incapable of binding to IKK. They identified NIK as a target of IKK and showed that phosphorylation of NIK by IKK 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-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-B Signaling Modulates NIK Stability Through IKK-Mediated Phosphorylation. Sci. Signal.3, ra41 (2010).