Original Article

Bruton's Tyrosine Kinase Is Required for Activation of IB Kinase and Nuclear Factor B in Response to B Cell Receptor Engagement

Correspondence to: Wasif N. Khan, Dept. of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel:615-343-5632 Fax:615-343-7392 E-mail:Khanwn{at}ctrvax.vanderbilt.edu.

Mutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progression, and proliferation in response to B cell antigen receptor (BCR) stimulation. BCR stimulation leads to the activation of transcription factor nuclear factor (NF)-B, which in turn regulates genes controlling B cell growth. We now demonstrate that a null mutation in btk known to cause the xid phenotype prevents BCR-induced activation of NF-B. This defect can be rescued by reconstitution with wild-type BTK. This mutation also interferes with BCR-directed activation of IB kinase (IKK), which normally targets the NF-B inhibitor IB for degradation. Taken together, these findings indicate that BTK couples IKK and NF-B to the BCR. Interference with this coupling mechanism may contribute to the B cell deficiencies observed in XLA and xid.

Key Words: X-linked immunodeficiency, X-linked agammaglobulinemia, antigen receptor signaling, transcription factor, Tec family tyrosine kinase

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