Fc gamma receptors differ in their structural requirements for interactionwith the tyrosine kinase Syk in the initial steps of signaling for phagocytosis

Receptors for the constant region of IgG, Fc gamma receptors, are expressed on the surface of hematopoietic cells, where they mediate signaling events , such as phagocytosis, essential for host defense. Fc gamma receptors also play a role in the pathophysiology of autoimmune diseases. We have demonst rated that members of each of the three classes of human Fc gamma receptors , Fc gamma RI, Fc gamma RII, and Fc gamma RIII, mediate phagocytosis, but t hat important differences exist in their requirements for phagocytic signal ing. For example, the Fc gamma receptors Fc gamma RI and Fc gamma RIIIA ind uce signaling largely by association with a gamma subunit containing a cons erved cytoplasmic motif (ITAM) whose tyrosines are phosphorylated following receptor stimulation. Fc gamma RIIA contains a similar moth in its own cyt oplasmic domain and does not require the gamma chain for phagocytic signali ng. The tyrosine kinase Syk associates with the cytoplasmic domain of both the Fc gamma receptor gamma chain and Fc gamma RIIA and is required for pha gocytosis by both Fc gamma receptor systems. To elucidate the differences i n phagocytic signaling by the gamma chain and Fc gamma RIIA, we investigate d the requirements for Fc gamma receptor/Syk co-immunoprecipitation, tyrosi ne phosphorylation, and phagocytosis, Both Fc gamma RIIA and the human gamm a chain contain a tyrosine seven amino acids upstream of the ITAM motif. We observed that the upstream tyrosine plays a role in Fc gamma RIIA phagocyt ic signaling but is not involved in phagocytic signaling by the human gamma chain. Our data also indicate that the two ITAM tyrosines of the human gam ma chain and Fc gamma RIIA do not contribute equally to Fc gamma receptor a ssociation with Syk kinase and phagocytic signaling. The data indicate that the carboxy-terminal tyrosine of the receptor cytoplasmic domain is especi ally important both for the interaction with Syk kinase and for phagocytosi s. Elucidating such differences in gamma chain and Fc gamma RIIA signaling may be valuable in designing strategies for therapeutic intervention in hem atopoietic and immunological disorders. (C) 2000 Academic Press.