Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.

Bruton's tyrosine kinase (Btk) is a recently described B-cell-specific tyrosine kinase. Mutations in this gene lead to human X chromosome-linked agammaglobulinemia and murine X-linked immunodeficiency. Although genetic evidence strongly suggests that Btk plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remains unknown, primarily because the proteins that it interacts with have not yet been identified. Here, we show that Btk interacts with Src homology 3 domains of Fyn, Lyn, and Hck, protein-tyrosine kinases that get activated upon stimulation of B- and T-cell receptors. These interactions are mediated by two 10-aa motifs in Btk. An analogous site with the same specificity is also present in Itk, the T-cell-specific homologue of Btk. Our data extend the range of interactions mediated by Src homology 3 domains and provide an indication of a link between Btk and established signaling pathways in B lymphocytes. IMAGES:

布鲁顿酪氨酸激酶（Bruton's tyrosine kinase, Btk）是近年发现的B细胞特异性酪氨酸激酶。该基因的突变可导致人类X连锁无丙种球蛋白血症（X chromosome-linked agammaglobulinemia）与小鼠X连锁免疫缺陷（murine X-linked immunodeficiency）。尽管遗传学证据强烈显示Btk在B淋巴细胞（B-lymphocyte）分化与活化过程中发挥关键作用，但其确切的作用机制仍未明确，这主要是由于其相互作用的蛋白质尚未被鉴定出来。本研究证实，Btk可与Fyn、Lyn及Hck的Src同源3结构域（Src homology 3 domains）结合，而这些蛋白酪氨酸激酶（protein-tyrosine kinases）在B细胞与T细胞受体受到刺激后会被激活。此类相互作用由Btk内的两个10氨基酸基序（10-aa motifs）介导。在Btk的T细胞特异性同源物Itk中，同样存在具有相同特异性的类似位点。本研究结果拓展了Src同源3结构域介导的相互作用范围，并提示Btk与B淋巴细胞中已确立的信号通路之间存在关联。IMAGES: