Authors:
Hisaaki Shinohara, Marcelo Behar, Kentaro Inoue, Michio Hiroshima, Tomoharu Yasuda, Takeshi Nagashima, Shuhei Kimura, Hideki Sanjo, Shiori Maeda, Noriko Yumoto, Sewon Ki, Shizuo Akira, Yasushi Sako, Alexander Hoffmann, Tomohiro Kurosaki, & Mariko Okada-Hatakeyama
Summary:
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.
Source:
Science; Vol. 344, No. 6185, 760-764 (05/16/14)