Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation.
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.
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Hisaaki
H
Shinohara
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA.
Marcelo
M
Behar
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Kentaro
K
Inoue
Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center (QBiC), 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan.
Michio
M
Hiroshima
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Tomoharu
T
Yasuda
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Takeshi
T
Nagashima
Graduate School of Engineering, Tottori University 4-101, Koyama-minami, Tottori 680-8552, Japan.
Shuhei
S
Kimura
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Hideki
H
Sanjo
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Shiori
S
Maeda
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Noriko
N
Yumoto
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Sewon
S
Ki
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Shizuo
S
Akira
Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan.
Yasushi
Y
Sako
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.
Alexander
A
Hoffmann
Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.
Tomohiro
T
Kurosaki
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.
Mariko
M
Okada-Hatakeyama
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D025461:Feedback, Physiological; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000819:agonists*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
D053468:CARD Signaling Adaptor Proteins; D006162:Guanylate Cyclase; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D012694:Serine; D000099151:MAP Kinase Kinase Kinase 7