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

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

Science (New York, N.Y.) (2014-05-17)
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
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.

MATERIALS
Product Number
Brand
Product Description

Serine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
L-Serine, Vetec, reagent grade, ≥99%
Sigma-Aldrich
L-Serine, BioUltra, ≥99.5% (NT)
Supelco
L-Serine, certified reference material, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Supelco
L-Serine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
L-Serine, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
L-Serine, from non-animal source, meets EP, USP testing specifications, suitable for cell culture, 98.5-101.0%