IBtk inhibits Btk signaling

Abstract

The members of the Tec family of tyrosine kinases contain Src homology 2 (SH2), SH3, and pleckstrin homology (PH) domains, in addition to their kinase domains. Unlike the Src family of tyrosine kinases, which have a negative regulatory tyrosine located at their COOH-termini, members of the Tec family do not have an obvious negative regulatory site. Liu et al. (News and Views by Koyasu) have now identified a protein, termed IBtk, that interacts with and inhibits Bruton's tyrosine kinase (Btk) activity. IBtk and Btk associated in vitro and in vivo; however, IBtk did not interact with the related Tec family kinase Itk, suggesting that IBtk might specifically interact with Btk. Chicken B cells transfected with IBtk exhibited reduced changes of calcium concentrations and inhibition of NF-κB activation, in response to B cell-receptor stimulation. Other experiments revealed that the COOH-terminal portion of IBtk bound the the PH domain of Btk, and was responsible for mediating the inhibtion of Btk activity. Activation of B cells led to the localization of Btk and IBtk to the plasma membrane, which suggests that IBtk might inhibit Btk activity soon after B cell receptor-dependent activation to tightly control Btk-mediated signaling. These data are likely to spur a search for specific inhibitors of other Tec family members. W. Liu, I. Quinto, X. Chen, C. Palmieri, R. L. Rabin, O. M. Schwartz, D. L. Nelson, G. Scala, Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein. Nature Immunol. 2 , 939-946 (2001). [Online Journal] S. Koyasu, Beating a kinase? Nature Immunol. 2 , 897-898 (2001). [Online Journal]