Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein

Bruton's tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase that is cru cial for human and murine B cell development, and its deficiency causes hum an X-linked agammaglobulinemia and murine X-linked immunodeficiency. In thi s report, we describe the function of the Btk-binding protein Sab SH3-domai n binding protein that preferentially associates with Btk, which we reporte d previously as a newly identified Src homology 3 domain-binding protein. S ab was shown to inhibit the auto- and transphosphorylation activity of Btk, which prompted us to propose that Sab functions as a transregulator of Btk . Forced overexpression of Sab in B cells led to the reduction of B cell an tigen receptor-induced tyrosine phosphorylation of Btk and significantly re duced both early and late B cell antigen receptor-mediated events, includin g calcium mobilization, inositol 1,4,5-trisphosphate production, and apopto tic cell death, where the involvement of Btk activity has been demonstrated previously. Together, these results indicate the negative regulatory role of Sab in the B cell cytoplasmic tyrosine kinase pathway.