Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain

Abstract

Bruton's agammaglobulinemia tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase important in B-lymphocyte development, differentiation, and signaling. Btk is a member of the Tec family of kinases. Mutations in the Btk gene lead to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Activation of Btk triggers a cascade of signaling events that culminates in the generation of calcium mobilization and fluxes, cytoskeletal rearrangements, and transcriptional regulation involving nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT). In B cells, NF-kappaB was shown to bind to the Btk promoter and induce transcription, whereas the B-cell receptor-dependent NF-kappaB signaling pathway requires functional Btk. Moreover, Btk activation is tightly regulated by a plethora of other signaling proteins including protein kinase C (PKC), Sab/SH3BP5, and caveolin-1. For example, the prolyl isomerase Pin1 negatively regulates Btk by decreasing tyrosine phosphorylation and steady state levels of Btk. It is intriguing that PKC and Pin1, both of which are negative regulators, bind to the pleckstrin homology domain of Btk. To this end, we describe here novel mutations in the pleckstrin homology domain investigated for their transforming capacity. In particular, we show that the mutant D43R behaves similar to E41K, already known to possess such activity.

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

“…Conversely, a complex B-cell phenotype characterized by reduced numbers of follicular B cells, elevated numbers of B-1 B cells and to some extent MZ B cells, B-cell hyper-responsiveness and auto-antibody formation is found in genetic changes that increase BCR signaling. These include gain-of-function mutants of Lyn or Plcg2, deficiency for PTEN, a lipid phosphatase that antagonizes PI3K activity, overexpression of CD19 or mutations that disable inhibitory signaling of membrane receptors such as CD22, Pir-B, Siglec-G and FcgRIIB or their downstream signaling molecules Shp1 or Ship [12][13][14][15][16][17][18][19][20][21].Btk is a member of the Tec protein tyrosine kinase family that mediates many aspects of B-cell development, survival and function [8,22]. Whereas in humans Btk mutations cause a severe arrest of B-cell development at the pre-B-cell stage leading to X-linked agammaglobulinemia, in the mouse there is only a mild pre-B-cell defect, differentiation of transitional into mature peripheral B cells is impaired and B-1 cells are lacking [23][24][25].…”

“…Btk is a member of the Tec protein tyrosine kinase family that mediates many aspects of B-cell development, survival and function [8,22]. Whereas in humans Btk mutations cause a severe arrest of B-cell development at the pre-B-cell stage leading to X-linked agammaglobulinemia, in the mouse there is only a mild pre-B-cell defect, differentiation of transitional into mature peripheral B cells is impaired and B-1 cells are lacking [23][24][25].…”

“…The pleckstrin homology domain mutant E41K-Btk displayed robust transformation potential in a soft-agar assay, increased membrane localization and phosphorylation in quiescent cells, independent of PI3K activity [26]. This capacity was augmented by mutation of the main autophosphorylation site in the SH3 domain, Y223F, although the role of Y223 phosphorylation for Btk function in vivo remains unclear [22,27]. We have previously reported that expression of Tg E41K-Btk throughout the B-cell lineage resulted in an almost complete deletion of immature B cells in the BM, irrespective of the presence of the endogenous intact Btk gene [28].…”

Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk

“…CRT normally is an endoplasmic reticulum (ER) protein possessing ER retention KDEL sequences but can be released to the cell surface in many instances of cell damage by cytotoxic drugs or inflammation and is recognized by macrophage LRP1/CD91 during phagocytosis of apoptotic cells (12,13). Bruton's tyrosine kinase (Btk) is a member of the Tec nonreceptor protein tyrosine kinase family, which plays a crucial role in the regulation of the innate immune response (14,15). A defect of Btk leads to immunodeficiencies including X-linked hypo-or agammaglobulinemia (16)(17)(18), presumably caused by the blockade of B-cell development and perhaps related to inefficient clearance of defective B-lineage cells as well (19).…”

Inhibitors of B-Cell Receptor Signaling for the Treatment of Chronic Lymphocytic Leukemia

“…Btk is primarily expressed in hematopoietic cells, and is important in B-lymphocyte development and differentiation [15,16]. It is required for B-cell maturation, and is overexpressed in a number of B-cell malignancies including CLL.…”