The Role of the Cytoplasmic Domain of the FcγRI α Chain in FcγRI Signaling.

The high affinity Fcγreceptor FcγRI, consists of a ligand binding α chain and an associated γ chain subunit. Signaling by FcγRI is thought to be mediated through the cytoplasmic domain (CYT) of the γ chain which contains the ITAM sequence essential for many Ig receptor signaling events. For example, we have demonstrated that the γ chain is required for FcγRI mediated phagocytosis. The FcγRI α chain CYT lacks known signaling motifs and consists of 64 amino acids whose function has not yet been defined. Evidence is beginning to accumulate, however, for the participation of the FcγRIα CYT in FcγRI mediated signaling events. For example, we previously demonstrated that the FcγRIα CYT contributes to modulation of FcγRI mediated cytokine release (eg IL-6) and calcium flux. We have now observed that in the absence of γchain expression, FcγRIα efficiently induces the internalization of aggregated IgG complexes in transfected COS-1 cells. Taken together, the data suggest that the FcγRIα CYT contributes to signaling by FcγRI. We, therefore, utilized yeast two-hybrid screening to identify effector molecules that bind to the FcγRIα CYT. Of especial interest among the identified binding molecules is β arrestin-2, recently defined as an adaptor molecule linking receptors such as the LDL and type III TGF-β receptors to the endocytic pathway. Also of interest is Snapin, an adaptor molecule involved in membrane trafficking. These studies should help to define sequences in the cytoplasmic domain of FcγRIα that mediate and/or modulate important FcγR functions.