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

Abstract

The low affinity receptor for IgG, FcgammaRIIB, 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 p21ras activation, though the basis of this inhibition is unknown. We show here that FcgammaRIIB-BCR coaggregation leads to increased tyrosine phosphorylation of the RasGAP-binding protein p62dok, 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 p62dok via the latter's phosphotyrosine-binding domain. Using chimeric FcgammaRIIB containing the RasGAP-binding domain of p62dok, we demonstrate that p62dok contains all structural information required to mediate the inhibitory effect of FcgammaRIIB on Erk activation.