Function of Bruton's tyrosine kinase during B cell development is partially independent of its catalytic activity
| Autor: | Gemma M. Dingjan, Alex Maas, Katarina Dahlenborg, Rudolf W. Hendriks, Sabine Middendorp |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Transgene
Immunology B-cell receptor Receptors Antigen B-Cell Mice Transgenic SH3 domain Mice Immunoglobulin lambda-Chains immune system diseases hemic and lymphatic diseases Catalytic Domain medicine Agammaglobulinaemia Tyrosine Kinase Immunology and Allergy Bruton's tyrosine kinase Animals Gene Rearrangement B-Lymphocyte Light Chain Humans B cell Cells Cultured B-Lymphocytes biology Autophosphorylation NF-kappa B Cell Differentiation Gene rearrangement Protein-Tyrosine Kinases Hematopoietic Stem Cells Molecular biology Mice Inbred C57BL medicine.anatomical_structure Gene Expression Regulation biology.protein Mutagenesis Site-Directed Tyrosine kinase Cell Division Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 171(11) |
| ISSN: | 0022-1767 |
| Popis: | The Tec family member Bruton’s tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase that transduces signals from the pre-B and B cell receptor (BCR). Btk is involved in pre-B cell maturation by regulating IL-7 responsiveness, cell surface phenotype changes, and the activation of λ L chain gene rearrangements. In mature B cells, Btk is essential for BCR-mediated proliferation and survival. Upon BCR stimulation, Btk is transphosphorylated at position Y551, which promotes its catalytic activity and subsequently results in autophosphorylation at position Y223 in the Src homology 3 domain. To address the significance of Y223 autophosphorylation and the requirement of enzymatic activity for Btk function in vivo, we generated transgenic mice that express the autophosphorylation site mutant Y223F and the kinase-inactive mutant K430R, respectively. We found that Y223 autophosphorylation was not required for the regulation of IL-7 responsiveness and cell surface phenotype changes in differentiating pre-B cells, or for peripheral B cell differentiation. However, expression of the Y223F-Btk transgene could not fully rescue the reduction of λ L chain usage in Btk-deficient mice. In contrast, transgenic expression of kinase-inactive K430R-Btk completely reconstituted λ usage in Btk-deficient mice, but the defective modulation of pre-B cell surface markers, peripheral B cell survival, and BCR-mediated NF-κB induction were partially corrected. From these findings, we conclude that: 1) autophosphorylation at position Y223 is not essential for Btk function in vivo, except for regulation of λ L chain usage, and 2) during B cell development, Btk partially acts as an adapter molecule, independent of its catalytic activity. |
| Databáze: | OpenAIRE |
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