Bruton tyrosine kinase

Bruton tyrosine kinase (Btk) is a 659 amino acid member of a recently identified subfamily of src-related cytoplasmic tyrosine kinases (Figure 1). It is expressed throughout B cell and myeloid development but it is not expressed in nonhematopoietic cells. Like src, Btk has a carboxy-terminal catalytic domain adjacent to SH2 and SH3 (src homology 2 and 3) domains. However, unlike src but similar to the other members of its subfamily, which include Tec, Itk and Bmx, Btk has an amino-terminal PH (pleckstrin homology) domain followed by a proline-rich region. Although the substrates phosphorylated by Btk have not yet been identified, like other tyrosine kinases, Btk is thought to function in signal transduction. This view is supported by the observation that the protein-protein interaction domains of Btk bind to other molecules known to be involved in signal transduction, including src family members, the j3y subunit of G proteins, protein kinase C and cbl.

Btk is phosphorylated and its kinase activity is increased by stimulation of a variety of cell surface receptors, including, and perhaps most importantly, the B cell receptor complex (BCR). After cross-linking of cell surface IgM, src family members phos-phorylate Btk, which then increases its catalytic activity by autophosphorylation. This process is associated with movement of Btk to the inner surface of the cell membrane.

The well-characterized murine immunodeficiency, xid, is caused by an amino acid substitution in the PH domain of Btk. The phenotype of the xid defect appears to be milder than the XLA defect. Mice with either the spontaneous Btk mutation or a null mutation in Btk induced by homologous recombination have reduced concentrations of serum IgM and IgG3 and they lack a mature population of B cells; however, they do have an antibody response to T cell-dependent antigens and they have relatively normal concentrations of serum IgGl, IgG2a and IgG2b. The phenotype of the xid mice suggests that Btk is required not only at the transition from pre-B cell to B cell but also at later stages of differentiation.

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