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

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