Posttranscriptional regulation of Bruton's tyrosine kinase expression in antigen receptor-stimulated splenic B cells

Sazuku Nisitani, Anne B. Satterthwaite, Koichi Akashi, Irving L. Weissman, Owen N. Witte, Matthew I. Wahl

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Abstract

Mutation of Bruton's tyrosine kinase (Btk) causes human X-linked agammaglobulinemia 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 sensitive intracellular immunofluorescent assay was developed to measure Btk protein on a per cell basis to test the hypothesis that its dosage is dynamically regulated during B cell development or functional responses. Marrow-derived hematopoietic stem cells, common lymphoid progenitor cells, and developing 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 xid mice. Activation of the B cell antigen receptor up-regulated Btk protein level 10- fold within several hours by a phosphatidylinositol 3-kinase-dependent, post- transcriptional mechanism. In contrast, the protein level of Btk R2BC in activated B lymphocytes from xid mice remained low. Bypass of the antigen receptor signaling pathways by treatment of cells with phorbol myristic acid and ionomycin rescued up-regulation of Btk protein in xid splenic B cells. These combined results suggest that certain receptor signals mediated by Btk regulate the level of expression of Btk protein in responding B lymphocytes to potentiate signal transduction. Dynamic regulation of Btk protein dosage is an additional mechanism to modulate B lymphocyte immune functions.

Original languageEnglish (US)
Pages (from-to)2737-2742
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number6
DOIs
StatePublished - Mar 14 2000

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Antigen Receptors
B-Lymphocytes
X-Linked Combined Immunodeficiency Diseases
Lymphoid Progenitor Cells
Proteins
Agammaglobulinaemia tyrosine kinase
Bone Marrow
Phosphatidylinositol 3-Kinase
B-Cell Antigen Receptors
Ionomycin
Hematopoietic Stem Cells
Signal Transduction
Up-Regulation

ASJC Scopus subject areas

  • Genetics
  • General

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Posttranscriptional regulation of Bruton's tyrosine kinase expression in antigen receptor-stimulated splenic B cells. / Nisitani, Sazuku; Satterthwaite, Anne B.; Akashi, Koichi; Weissman, Irving L.; Witte, Owen N.; Wahl, Matthew I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 6, 14.03.2000, p. 2737-2742.

Research output: Contribution to journalArticle

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