Phospholipase C- gamma 2 Couples Bruton's Tyrosine Kinase to the NF- Kappa B Signaling Pathway in B Lymphocytes

Mutations in the gene encoding Bruton's tyrosine kinase (BTK) interfere with B cell proliferation and lead to an X-linked immunodeficiency in mice characterized by reduced B cell numbers. Recent studies have established that BTK transmits signals from the B cell antigen receptor (BCR) to transcription factor NF- Kappa B, which in turn reprograms a set of genes required for normal B cell growth. We now demonstrate that induction of NF- Kappa B via this pathway requires the intermediate action of the - gamma 2 isoform of phospholipase C (PLC- gamma 2), a potential phosphorylation substrate of BTK. Specifically, pharmacologic agents that block the action of either PLC- gamma 2 or its second messengers prevent BCR-induced activation of I Kappa B kinase. Moreover, activation of NF- Kappa B in response to BCR signaling is completely abolished in B cells deficient for PLC- gamma 2. Taken together, these findings strongly suggest that PLC- gamma 2 functions as an integral component of the BTK/NF- Kappa B axis following BCR ligation. Interference with this NF- Kappa B cascade may account for some of the B cell defects reported for plc- gamma 2 super(-/-) mice, which develop an X-linked immunodeficiency-like phenotype.