BINDING OF BRUTONS 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-li nked 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 a ction remains unknown, primarily because the proteins that it interact s with have not yet been identified. Here, we show that Btk interacts with Src homology 3 domains of Fyn, Lyn, and Hck, protein-tyrosine kin ases that get activated upon stimulation of B- and T-cell receptors. T hese interactions are mediated by two 10-aa motifs in Btk. An analogou s site with the same specificity is also present in Itk, the T-cell-sp ecific homologue of Btk. Our data extend the range of interactions med iated by Src homology 3 domains and provide an indication of a link be tween Btk and established signaling pathways in B lymphocytes.