Bruton's tyrosine kinase links the B cell receptor to nuclear factor kappaB activation

The recognition of antigen by membrane immunoglobulin M (mIgM) results in a complex series of signaling events in the cytoplasm leading to gene activa tion. Bruton's tyrosine kinase (BTK), a member of the Tec family of tyrosin e kinases, is essential for the full repertoire of IgM signals to be transd uced. We examined the ability of BTK to regulate the nuclear factor (NF)-ka ppa B/Rel family of transcription factors, as the activation of these facto rs is required for a B cell response to mIgM. We found greatly diminished I gM- but not CD40-mediated NF-kappa B/Rel nuclear translocation and DNA bind ing in B cells from X-linked immunodeficient (xid) mice that harbor an R28C mutation in btk, a mutation that produces a functionally inactive kinase. The defect was due, in part, to a failure to fully degrade the inhibitory p rotein of NF-kappa B, I kappa B alpha. Using a BTK-deficient variant of DT4 0 chicken B cells, we found that expression of wild-type or gain-of-functio n mutant BTK, but not the R28C mutant, reconstituted NF-kappa B activity. T hus, BTK is essential for activation of NF-kappa B via the B cell receptor.