Reference - Detail
|Author||Antony P, Petro JB, Carlesso G, Shinners NP, Lowe J, Khan WN.|
|Title||B cell receptor directs the activation of NFAT and NF-kappaB via distinct molecular mechanisms.|
|Journal||Exp Cell Res|
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.
|MeSH||Agammaglobulinaemia Tyrosine Kinase Animals B-Lymphocytes / drug effects B-Lymphocytes / metabolism CD5 Antigens / biosynthesis CD5 Antigens / genetics 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|
|WOS Category||ONCOLOGY CELL BIOLOGY|
|Human and Animal Cells|