Activating Fc gamma R function depends on endosomal-signaling platforms

Cell surface receptor internalization can either terminate signaling or activate alternative endosomal signaling pathways. We investigated here whether endosomal signaling is involved in the function of the human receptors for Fc immunoglobulin fragments (FcRs): Fc alpha RI, Fc gamma RIIA, and Fc gamma RI. All these receptors were internalized after their cross-linking with receptor-specific antibodies, but their intracellular trafficking was different. Fc alpha RI was targeted directly to lysosomes, while Fc gamma RIIA and Fc gamma RI were internalized in particular endosomal compartments described by the insulin responsive aminopeptidase (IRAP), where they recruited signaling molecules, such as the active form of the kinase Syk, PLCg and the adaptor LAT. Destabilization of Fc gamma R endosomal signaling in the absence of IRAP compromised cytokine secretion downstream Fc gamma R activation and macrophage ability to kill tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Our results indicate that Fc gamma R endosomal signaling is required for the Fc gamma R-driven inflammatory reaction and possibly for the therapeutic action of monoclonal antibodies.