The RasGAP-binding protein p62dok is a mediator of inhibitory FcγRIIB signals in B cells

The low affinity receptor for IgG, Fc gamma RIIB, functions to dampen the antibody response and reduce the risk of autoimmunity. This function is reportedly mediated in part by inhibition of B cell antigen receptor (BCR)mediated 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 and tyrosine phosphorylation of the phosphatidylinositol 5-phosphatase SHIP, which further recruits p62(dok) via the latter's phosphotyrosine-binding domain. Using chimeric Fc gamma RIIB containing the RasGAP-binding domain of p62dok, we demonstrate that p62(dok) contains all structural information required to mediate the inhibitory effect of Fc gamma RIIB on Erk activation.