Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation

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

Research output: Contribution to journalArticle

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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-b (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.

Original languageEnglish
Pages (from-to)760-764
Number of pages5
JournalScience
Volume344
Issue number6185
DOIs
Publication statusPublished - Jan 1 2014

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B-Lymphocytes
Phosphotransferases
Guanylate Kinases
Serine
Phosphorylation
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • General

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Shinohara, H., Behar, M., Inoue, K., Hiroshima, M., Yasuda, T., Nagashima, T., ... Okada-Hatakeyama, M. (2014). Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation. Science, 344(6185), 760-764. https://doi.org/10.1126/science.1250020

Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation. / Shinohara, Hisaaki; Behar, Marcelo; Inoue, Kentaro; Hiroshima, Michio; Yasuda, Tomoharu; Nagashima, Takeshi; Kimura, Shuhei; Sanjo, Hideki; Maeda, Shiori; Yumoto, Noriko; Ki, Sewon; Akira, Shizuo; Sako, Yasushi; Hoffmann, Alexander; Kurosaki, Tomohiro; Okada-Hatakeyama, Mariko.

In: Science, Vol. 344, No. 6185, 01.01.2014, p. 760-764.

Research output: Contribution to journalArticle

Shinohara, H, Behar, M, Inoue, K, Hiroshima, M, Yasuda, T, Nagashima, T, Kimura, S, Sanjo, H, Maeda, S, Yumoto, N, Ki, S, Akira, S, Sako, Y, Hoffmann, A, Kurosaki, T & Okada-Hatakeyama, M 2014, 'Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation', Science, vol. 344, no. 6185, pp. 760-764. https://doi.org/10.1126/science.1250020
Shinohara H, Behar M, Inoue K, Hiroshima M, Yasuda T, Nagashima T et al. Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation. Science. 2014 Jan 1;344(6185):760-764. https://doi.org/10.1126/science.1250020
Shinohara, Hisaaki ; Behar, Marcelo ; Inoue, Kentaro ; Hiroshima, Michio ; Yasuda, Tomoharu ; Nagashima, Takeshi ; Kimura, Shuhei ; Sanjo, Hideki ; Maeda, Shiori ; Yumoto, Noriko ; Ki, Sewon ; Akira, Shizuo ; Sako, Yasushi ; Hoffmann, Alexander ; Kurosaki, Tomohiro ; Okada-Hatakeyama, Mariko. / Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation. In: Science. 2014 ; Vol. 344, No. 6185. pp. 760-764.
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