Studies have shown that loss of CD45 expression leads to aberrant signaling via the B cell antigen receptor (BCR). Although phospholipase C gamma activation and the production of inositol 1,4,5-triphosphate appear to be relatively normal, calcium mobilization is significantly impaired. Specifically, cross-linking of the BCR leads to mobilization of calcium from intracellular stores, but does not promote extracellular influx of calcium. Previous studies have shown that cross-linking of the BCR induces tyrosine phosphorylation of CD22 promoting its interaction with SH2 domain-containing effector proteins. Analysis of CD22 phosphorylation in CD45-negative B cells demonstrated that it is hyper-phosphorylated on tyrosine in unstimulated cells, and exhibits increased inducible phosphorylation in response to cross-linking of the BCR. Additional support for the role of CD45 in regulating the phosphorylation of CD22 and its interaction with the phosphatase SHP-1 was obtained from experiments in which CD45 cross-linking was observed to promote increased phosphorylation of CD22 and binding of SHP-1. Although cross-linking of CD45 resulted in its capping within the membrane, little or no CD22 was observed to co-cap. Thus, it is possible that cross-linking of CD45 physically restricted its ability to interact with CD22 thereby altering its phosphorylation state. Furthermore, because hyperphosphorylation of CD22 in CD45-negative cells was observed in connection with increased recruitment of SHP-1, it is possible that this interaction may play a role in negatively regulating calcium mobilization in response to BCR cross-linking.