The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development

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Abstract
Upon B‐cell antigen receptor (BCR) activation, the protein tyrosine kinase Syk phosphorylates the adaptor protein SH2 domain‐containing leukocyte protein of 65 kDa (SLP‐65), thus coupling the BCR to diverse signalling pathways. Here, we report that SLP‐65 is not only a downstream target and substrate of Syk but also a direct binding‐partner and activator of this kinase. This positive feedback is mediated by the binding of the SH2 domain of SLP‐65 to an autophosphorylated tyrosine of Syk. The mutant B cells that cannot form the Syk/SLP‐65 complex are defective in BCR‐induced extracellular signal‐regulated kinase, nuclear factor κ B and nuclear factor of activated T cells, but not Akt activation, and are blocked in B‐cell development. Furthermore, we show that formation of the Syk/SLP‐65 complex is required for sustained Ca2+ responses in activated B cells. We suggest that after activation and internalization of the BCR, Syk remains active as part of a membrane‐bound Syk/SLP‐65 complex controlling sustained signalling and calcium influx.