The B cell antigen receptor (BCR)–mediated activation of IκB kinase (IKK) and nuclear factor–κB require protein kinase C (PKC)β; however, the mechanism by which PKCβ regulates IKK is unclear. Here, we demonstrate that another protein kinase, TGFβ-activated kinase (TAK)1, is essential for IKK activation in response to BCR stimulation. TAK1 interacts with the phosphorylated CARMA1 (also known as caspase recruitment domain [CARD]11, Bimp3) and this interaction is mediated by PKCβ. IKK is also recruited to the CARMA1–Bcl10–mucosal-associated lymphoid tissue 1 adaptor complex in a PKCβ-dependent manner. Hence, our data suggest that phosphorylation of CARMA1, mediated by PKCβ, brings two key protein kinases, TAK1 and IKK, into close proximity, thereby allowing TAK1 to phosphorylate IKK.

B‐cell activation mediated through the antigen receptor is dependent on activation of protein tyrosine kinases (PTKs) such as Lyn and Syk and subsequent phosphorylation of various signaling proteins. Here we report on the identification and characterization of the B‐cell scaffold protein with ankyrin repeats (BANK), a novel substrate of tyrosine kinases. BANK is expressed in B cells and is tyrosine phosphorylated upon B‐cell antigen receptor (BCR) stimulation, which is mediated predominantly by Syk. Overexpres sion of BANK in B cells leads to enhancement of BCR‐induced calcium mobilization. We found that both Lyn and inositol 1,4,5‐trisphosphate receptor (IP3R) associate with the distinct regions of BANK and that BANK promotes Lyn‐mediated tyrosine phosphorylation of IP3R. Given that IP3R channel activity is up‐regulated by its tyrosine phosphorylation, BANK appears to be a novel scaffold protein regulating BCR‐induced calcium mobilization by connecting PTKs to IP3R. Because BANK expression is confined to functional BCR‐expressing B cells, BANK‐mediated calcium mobilization may be specific to foreign antigen‐induced immune responses rather than to signaling required for B‐cell development.