Fcγ Receptors Differ in Their Structural Requirements for Interaction with the Tyrosine Kinase Syk in the Initial Steps of Signaling for Phagocytosis

Receptors for the constant region of IgG, Fcγ receptors, are expressed on the surface of hematopoietic cells, where they mediate signaling events, such as phagocytosis, essential for host defense. Fcγ receptors also play a role in the pathophysiology of autoimmune diseases. We have demonstrated that members of each of the three classes of human Fcγ receptors, FcγRI, FcγRII, and FcγRIII, mediate phagocytosis, but that important differences exist in their requirements for phagocytic signaling. For example, the Fcγ receptors FcγRI and FcγRIIIA induce signaling largely by association with a γ subunit containing a conserved cytoplasmic motif (ITAM) whose tyrosines are phosphorylated following receptor stimulation. FcγRIIA contains a similar motif in its own cytoplasmic domain and does not require the γ chain for phagocytic signaling. The tyrosine kinase Syk associates with the cytoplasmic domain of both the Fcγ receptor γ chain and FcγRIIA and is required for phagocytosis by both Fcγ receptor systems. To elucidate the differences in phagocytic signaling by the γ chain and FcγRIIA, we investigated the requirements for Fcγ receptor/Syk co-immunoprecipitation, tyrosine phosphorylation, and phagocytosis. Both FcγRIIA and the human γ chain contain a tyrosine seven amino acids upstream of the ITAM motif. We observed that the upstream tyrosine plays a role in FcγRIIA phagocytic signaling but is not involved in phagocytic signaling by the human γ chain. Our data also indicate that the two ITAM tyrosines of the human γ chain and FcγRIIA do not contribute equally to Fcγ receptor association with Syk kinase and phagocytic signaling. The data indicate that the carboxy-terminal tyrosine of the receptor cytoplasmic domain is especially important both for the interaction with Syk kinase and for phagocytosis. Elucidating such differences in γ chain and FcγRIIA signaling may be valuable in designing strategies for therapeutic intervention in hematopoietic and immunological disorders.