MAJOR HISTOCOMPATIBILITY CLASS II-MEDIATED SIGNAL-TRANSDUCTION IS REGULATED BY THE PROTEIN-TYROSINE-PHOSPHATASE CD45

Major histocompatibility complex class II molecules and the B cell ant igen receptor (BCR) transduce similar signals when cross-linked by Lig and, Therefore, studies were conducted to determine whether the protei n tyrosine phosphatase CD45 regulates signaling via these transmembran e receptors in an analogous manner. Cross-linking of either class II m olecules or the BCR on CD45-positive K46-17 mu m lambda B lymphoma cel ls was observed to induce activation of the Src family protein-tyrosin e kinase Lyn, tyrosine phosphorylation of Syk and phospholipase C gamm a, and the production of inositol 1,4,5-trisphosphate leading to intra cellular mobilization as well as extracellular influx of Ca2+. In the absence of CD45, cross-linking of either class II molecules or the BCR failed to induce activation of Lyn, Syk was inducibly phosphorylated on tyrosine in a normal manner, whereas phospholipase C gamma exhibite d a high basal level of tyrosine phosphorylation that was not signific antly increased upon stimulation. Nevertheless, phospholipase C gamma appeared to be functional because CD45-negative cells produced elevate d levels of inositol 1,4,5-trisphosphate following stimulation through class II or the BCR, Regardless of this, CD45-negative cells exhibite d Ca2+ mobilization responses that were greatly diminished and transie nt in nature. Whereas little or no mobilization of Ca2+ was observed i n response to class II cross-linking, CD45-deficient cells mobilized C a2+ from intracellular stores but not the extracellular environment in response to BCR cross-linking. These results demonstrate that CD45 re gulates both Src family kinase activation and Ca2+ mobilization associ ated with class II-and BCR-mediated signal transduction.