The RasGAP-binding protein p62(dok) is a mediator of inhibitory Fc gamma RIIB signals in B cells

The low affinity receptor for IgG, Fc gamma RIIB, functions to dampen the a ntibody response and reduce the risk of autoimmunity. This function is repo rtedly mediated in part by inhibition of B cell antigen receptor (BCR)media ted p21(ras) activation, though the basis of this inhibition is unknown. We show here that Fc gamma RIIB-BCR coaggregation leads to increased tyrosine phosphorylation of the RasGAP-binding protein p62(dok), with a concomitant increase in its binding to RasGAP. These effects require the recruitment a nd tyrosine phosphorylation of the phosphatidylinositol 5-phosphatase SHIP, which further recruits p62(dok) via the latter's phosphotyrosine-binding d omain. Using chimeric Fc gamma RIIB containing the RasGAP-binding domain of p62dok, we demonstrate that p62(dok) contains all structural information r equired to mediate the inhibitory effect of Fc gamma RIIB on Erk activation .