B Cell receptor directs the activation of NFAT and NF-κB via distinct molecular mechanisms

Pierre Antony, James B. Petro, Gianluca Carlesso, Nicholas P. Shinners, John Lowe, Wasif N. Khan

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

BCR engagement initiates intracellular calcium ([Ca2+]i) mobilization which is critical for the activation of multiple transcription factors including NF-κB and NFAT. Previously, we showed that Bruton's tyrosine kinase (BTK)-deficient (btk-/-) B cells, which display a modestly reduced calcium response to BCR crosslinking, do not activate NF-κB. Here we show that BTK is also essential for the activation of NFAT following BCR engagement. Pharmacological mobilization of [Ca2+]i in BTK-deficient DT40 B cells (DT40.BTK) does not rescue BCR directed activation of NF-κB and only partially that of NFAT, suggesting existence of additional BTK-signaling pathways in this process. Therefore, we investigated a requirement for BTK in the production of diacylglycerol (DAG). We found that DT40.BTK B cells do not produce DAG in response to BCR engagement. Pharmacological inhibition of PKC isozymes and Ras revealed that the BCR-induced activation of NF-κB requires conventional PKCβ, whereas that of NFAT may involve non-conventional PKCδ and Ras pathways. Consistent with an essential role for BTK in the regulation of NFAT, B cells from btk-/- mice display defective expression of CD5, a gene under the control of NFAT. Together, these results suggest that BCR employs distinct BTK-dependent molecular mechanisms to regulate the activation of NF-κB versus NFAT.

Original languageEnglish (US)
Pages (from-to)11-24
Number of pages14
JournalExperimental Cell Research
Volume291
Issue number1
DOIs
StatePublished - Nov 15 2003
Externally publishedYes

Keywords

  • B-lymphocytes
  • Bruton's tyrosine kinase
  • Calcium
  • Diacylglycerol
  • NF-κB
  • NFAT
  • Phospholipase C-γ2
  • Signal transduction
  • Transcription factors
  • Transgenic/knockout
  • X-linked immunodeficiency

ASJC Scopus subject areas

  • Cell Biology

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