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10.1074/jbc.M115.713008

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suck abstract from ncbi


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pmid26826124      J+Biol+Chem 2016 ; 291 (16): 8440-52
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  • T Cell Receptor-induced Nuclear Factor ?B (NF-?B) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry* #MMPMID26826124
  • Liu X; Berry CT; Ruthel G; Madara JJ; MacGillivray K; Gray CM; Madge LA; McCorkell KA; Beiting DP; Hershberg U; May MJ; Freedman BD
  • J Biol Chem 2016[Apr]; 291 (16): 8440-52 PMID26826124show ga
  • T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular Ca2+ to activate the key transcription factors nuclear factor of activated T lymphocytes (NFAT) and NF-?B. The mechanism of NFAT activation by Ca2+ has been determined. However, the role of Ca2+ in controlling NF-?B signaling is poorly understood, and the source of Ca2+ required for NF-?B activation is unknown. We demonstrate that TCR- but not TNF-induced NF-?B signaling upstream of I?B kinase activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent Ca2+ release-activated Ca2+/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-?B protein p65 on Ser-536 and that this posttranslational modification controls its nuclear localization and transcriptional activation. Notably, our data reveal that this role for Ca2+ is entirely separate from its upstream control of I?B? degradation, thereby identifying a novel Ca2+-dependent distal step in TCR-induced NF-?B activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKC?-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR-induced NF-?B activation and define a new distal Ca2+-dependent checkpoint in TCR-induced NF-?B signaling that has broad implications for the control of immune cell development and T cell functional specificity.
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