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PMID:14597404

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Citation

Antony, P, Petro, JB, Carlesso, G, Shinners, NP, Lowe, J and Khan, WN (2003) B cell receptor directs the activation of NFAT and NF-kappaB via distinct molecular mechanisms. Exp. Cell Res. 291:11-24

Abstract

BCR engagement initiates intracellular calcium ([Ca2+]i) mobilization which is critical for the activation of multiple transcription factors including NF-kappaB 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-kappaB. 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-kappaB 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-kappaB requires conventional PKCbeta, whereas that of NFAT may involve non-conventional PKCdelta 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-kappaB versus NFAT.

Links

PubMed

Keywords

Animals; Antigens, CD5/biosynthesis; Antigens, CD5/genetics; B-Lymphocytes/drug effects; B-Lymphocytes/metabolism; Calcium Signaling/drug effects; Calcium Signaling/physiology; Cell Line; Chickens; DNA-Binding Proteins/drug effects; DNA-Binding Proteins/metabolism; Diglycerides/biosynthesis; Enzyme Inhibitors/pharmacology; Isoenzymes/antagonists & inhibitors; Isoenzymes/metabolism; Lymphocyte Activation/drug effects; Lymphocyte Activation/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B/drug effects; NF-kappa B/metabolism; NFATC Transcription Factors; Nuclear Proteins; Phospholipase C gamma; Protein Kinase C/antagonists & inhibitors; Protein Kinase C/metabolism; Protein-Tyrosine Kinases/deficiency; Protein-Tyrosine Kinases/genetics; Receptors, Antigen, B-Cell/drug effects; Receptors, Antigen, B-Cell/metabolism; Transcription Factors/drug effects; Transcription Factors/metabolism; Type C Phospholipases/antagonists & inhibitors; Type C Phospholipases/metabolism; ras Proteins/antagonists & inhibitors; ras Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


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References

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