S. Nisitani et al., Posttranscriptional regulation of Bruton's tyrosine kinase expression in antigen receptor-stimulated splenic B cells, P NAS US, 97(6), 2000, pp. 2737-2742
Citations number
56
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Mutation of Bruton's tyrosine kinase (Btk) causes human X-linked agammaglob
ulinemia and murine X-linked immunodeficiency syndrome (xid), Quantitative
aspects of B lymphocyte development and function have been demonstrated to
depend on Btk level in vivo by using a murine transgenic model system. A se
nsitive intracellular immunofluorescent assay was developed to measure Btk
protein on a per cell basis to test the hypothesis that its dosage is dynam
ically regulated during B cell development or functional responses, Marrow-
derived hematopoietic stem cells, common lymphoid progenitor cells, and dev
eloping B and myeloid lineages expressed Btk protein at comparable levels,
Resting peripheral B lineage cells had a significantly lower amount of Btk
than marrow-derived cells in both wild-type and rid mice. Activation of the
B cell antigen receptor up-regulated Btk protein level 10-fold within seve
ral hours by a phosphatidylinositol 3-kinase-dependent, posttranscriptional
mechanism, In contrast, the protein level of Btk R28C in activated B lymph
ocytes from rid mice remained low. Bypass of the antigen receptor signaling
pathways by treatment of cells with phorbol myristic acid and ionomycin re
scued up-regulation of Btk protein in rid splenic B cells. These combined r
esults suggest that certain receptor signals mediated by Btk regulate the l
evel of expression of Btk protein in responding B lymphocytes to potentiate
signal transduction, Dynamic regulation of Btk protein dosage is an additi
onal mechanism to modulate B lymphocyte immune functions.