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 demonstrated 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 that important differences exist in their requirements for phagocytic signaling. For example, the
Fc gamma receptors Fc gamma RI and Fc gamma RIIIA induce signaling largely by association with a gamma subunit containing a conserved cytoplasmic motif (ITAM) whose tyrosines are phosphorylated following receptor stimulation.
Fc gamma RIIA contains a similar motif in its own cytoplasmic domain and does not require the gamma chain for phagocytic signaling. 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 phagocytosis by both
Fc gamma receptor systems. To elucidate the differences in phagocytic signaling by the gamma chain and
Fc gamma RIIA, we investigated the requirements for
Fc gamma receptor/Syk co-immunoprecipitation,
tyrosine phosphorylation, and phagocytosis. Both
Fc gamma RIIA and the human gamma 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 phagocytic 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 gamma chain and
Fc gamma RIIA do not contribute equally to
Fc gamma 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 gamma chain and
Fc gamma RIIA signaling may be valuable in designing strategies for therapeutic intervention in hematopoietic and immunological disorders.