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Btk regulation in human and mouse B cells via protein kinase C phosphorylation of IBtkγ.
- Source :
-
Blood . 6/16/2011, Vol. 117 Issue 24, p6520-6531. 12p. - Publication Year :
- 2011
-
Abstract
- The inhibitor of Bruton tyrosine kinase γ (IBtkγ) is a negative regulator of the Bruton tyrosine kinase (Btk), which plays a major role in B-cell differentiation; however, the mechanisms of IBtkγ-mediated regulation of Btk are unknown. Here we report that B-cell receptor (BCR) triggering caused serine-phosphorylation of IBtkγ at protein kinase C consensus sites and dissociation from Btk. By liquid chromatography and mass-mass spectrometry and functional analysis, we identified IBtkγ-S87 and -S90 as the critical amino acid residues that regulate the IBtkγ binding affinity to Btk. Consistently, the mutants IBtkγ carrying S87A and S90A mutations bound constitutively to Btk and down-regulated Ca2+ fluxes and NF-κB activation on BCR triggering. Accordingly, spleen B cells from Ibtkγ-/- mice showed an increased activation of Btk, as evaluated by Y551-phosphorylation and sustained Ca2+ mobilization on BCR engagement. These findings identify a novel pathway of Btk regulation via protein kinase C phosphorylation of IBtkγ. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00064971
- Volume :
- 117
- Issue :
- 24
- Database :
- Academic Search Index
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 66818332
- Full Text :
- https://doi.org/10.1182/blood-2010-09-308080