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Positive Feedback Within a Kinase Signaling Complex Functions as a Switch Mechanism for NF-κB Activation

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Science  16 May 2014:
Vol. 344, Issue 6185, pp. 760-764
DOI: 10.1126/science.1250020

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Signaling Dynamics

The signaling pathways that activate the transcription factor NF-κB are key regulatory pathways in cells of the immune system, and their dynamic properties are still being elucidated. In B cells, analysis of single-cell responses has shown that the stimulation of the B cell receptor causes a “digital” all-or-none response of cells to a stimulus. Shinohara et al. (p. 760) used a combination of mathematical modeling and experiments to show that this property of the system results from the presence of a positive feedback loop among the signaling components activated in response to the receptor. Studies in cells expressing mutated signaling components resolved key phosphorylation events that provide the threshold responses observed and identified potential molecular modifications that might modify the threshold or other aspects of the dynamic response.

Abstract

A switchlike response in nuclear factor–κB (NF-κB) activity implies the existence of a threshold in the NF-κB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)–TAK1 (MAP3K7)–inhibitor of NF-κB (IκB) kinase-β (IKKβ) module is a switch mechanism for NF-κB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKβ to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKβ target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-κB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.

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