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

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.

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

“…Activation by trans-autophosphorylation is a positive feedback mechanism for a switch-like response to signal (Shinohara et al, 2014). By requiring the peripheral site to bind a PIP 3 for activation by dimerization, the Btk PH-TH module creates an even sharper PIP 3 concentration threshold for activation.…”

Cellular Decision Making by Non-Integrative Processing of TLR Inputs

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“…We found marked similarities in the gene-expression profiles of LMP2A-and BCR-activated B cells (Fig. S6) (47). However, quantitative analysis of these gene expressions will be required to confirm these possibilities.…”