2 DISTINCT REGIONS OF FC-GAMMA-RI INITIATE SEPARATE SIGNALING PATHWAYS INVOLVED IN ENDOCYTOSIS AND PHAGOCYTOSIS

Cross-linking of the high affinity receptor for IgG, Fc gamma RI, can result in both endocytosis of immune complexes and phagocytosis of ops onized particles in myeloid cells, although the cytoplasmic domain of the receptor lacks the tyrosine activation motif which has been implic ated in signal transduction triggered by cross-linking of other Fc rec eptors. To identify the structural determinants of Fc gamma RI-mediate d ligand internalization, we have expressed Fc gamma RI or truncated v ersions of Fc gamma RI in COS cells, either alone or in the presence o f the Fc epsilon RI gamma subunit (which contains a classical tyrosine activation motif and associates with Fc gamma RI in myeloid cells), a nd assessed their ability to mediate endocytosis and phagocytosis. We have found that Fc gamma RI alone (in the absence of the gamma subunit ) is capable of mediating endocytosis in COS cells and that the proces s occurs via a novel, tyrosine kinase-independent signalling pathway. Activation of this pathway following cross-linking appears to require only the receptor extracellular domain. In contrast, Fc gamma RI phago cytic function in COS cells is dependent on an interaction between the receptor transmembrane domain and the gamma subunit and is mediated b y recruitment of tyrosine kinase activity. Our data therefore indicate that distinct domains of the receptor regulate ligand internalization following receptor cross-linking by either immune complexes (endocyto sis) or opsonized particles (phagocytosis) and that these functions ar e mediated by different intracellular signalling pathways.