Reconstitution of Btk signaling by the atypical Tec family tyrosine kinases Bmx and Txk

Bruton's tyrosine kinase (Btk) is mutated in X-linked agammaglobulinemia pa tients and plays an essential role in B cell receptor signal transduction, Btk is a member of the Tec family of nonreceptor protein-tyrosine kinases t hat includes Bmx, Itk, Tec, and Txk. Cell lines deficient for Btk are impai red in phospholipase C-gamma 2 (PLC gamma 2)-dependent signaling. Itk and T ec have recently been shown to reconstitute PLC gamma 2-dependent signaling in Btk-deficient human cells, but it is not knows whether the atypical Tec family members, Bmx and Txk, can reconstitute function. Here we reconstitu te Btk-deficient DT40 B cells with Bmx and Txk to compare their function wi th other Tec kinases, We show that in common with Itk and Tee, Bmx reconsti tuted PLC gamma 2-dependent responses including calcium mobilization, extra cellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MA PK) activation, and apoptosis, Txk also restored PLC gamma 2/calcium signal ing but, unlike other Tec kinases, functioned in a phosphatidylinositol 3-k inase-independent manner and failed to reconstitute apoptosis. These result s are consistent with a common role for Tec kinases as amplifiers of PLC ga mma 2-dependent signal transduction, but suggest that the pleckstrin homolo gy domain of Tec kinases, absent in Txk, is essential for apoptosis.