Binding of Bruton's Tyrosine Kinase to Fyn, Lyn, or Hck Through a Src Homology 3 Domain-Mediated Interaction

Abstract

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.

Additional Information

© 1994 by National Academy of Sciences Contributed by David Baltimore, April 25, 1994 We thank Dr. Roger Brent for kindly providing us with the yeast two-hybrid system; Dr. Marius Sudol for providing the chicken Fyn cDNA; Drs. Lei Ron, Russ Finley, and Erica Golemis for technical advice; Drs. Ruibao Ren, Patricia Cortes, and Joshy Jacob for suggestions; and Warren Pear, Benjamin Chen, and Kalle Saksela for manuscript assistance. G.C. and Z.-S.Y. are recipients of an Irvington House Institute fellowship and a Leukemia Society special fellowship, respectively. This work was supported by National Institute of Allergy and Infectious Diseases Grant A122346 to D.B. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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