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B Kinase/IB
/NF-B without the Need for PI3K and Phospholipase C
1
,
Departments of*
Medicine and Microbiology, Boston University School of Medicine, and Immunobiology Unit, Evans Memorial Department of Clinical Research, Boston University Medical Center, Boston, MA 02118
BCR signaling is propagated by a series of intermediaries and eventuates in NF-
B activation, among other outcomes. Interruption of several mediators that constitute the signalosome, such as PI3K and phospholipase C
2, completely blocks BCR signaling for NF-B. We show here that this accepted, conventional paradigm is, in fact, limited to naive B cells. CD40L treatment reprograms normal B cells such that a novel, alternate pathway for BCR signaling is created. Through this alternate pathway BCR triggering induces nuclear NF-B without the need for PI3K or for phospholipase C2. Induction of NF-B via the alternate pathway is accompanied by IB kinase 
(IKK) phosphorylation, IB
phosphorylation, and IB degradation, and inhibition of IKK blocked IB degradation. Several key events in the conventional pathway, including early protein tyrosine phosphorylation, were unimpeded by generation of the alternate pathway which appears to operate in parallel, rather than in competition, with classical BCR signaling. These results demonstrate cross-talk between CD40 and BCR, such that the requirements for BCR signaling are altered by prior B cell exposure to CD40L. The alternate BCR signaling pathway bypasses multiple signalosome elements and terminates in IKK activation.
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