Two distinct regions of FC gamma RI initiate separate signalling 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 opsonized particles in myeloid cells, although the cytoplasmic domain of the receptor lacks the tyrosine activation motif which has been implicated in signal transduction triggered by cross-linking of other Fc receptors. To identify the structural determinants of Fc gamma RI-mediated ligand internalization, we have expressed Fc gamma RI or truncated versions of Fc gamma RI in COS cells, either alone or in the presence of the Fc epsilon RI gamma subunit (which contains a classical tyrosine activation motif and associates with Fc gamma RI in myeloid cells), and 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 process 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 phagocytic function in COS cells is dependent on an interaction between the receptor transmembrane domain and the gamma subunit and is mediated by 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 (endocytosis) or opsonized particles (phagocytosis) and that these functions are mediated by different intracellular signalling pathways.
Physiological Laboratory, University of Cambridge, UK.
W
W
Davis
P T
PT
Harrison
M J
MJ
Hutchinson
J M
JM
Allen
D000818:Animals; D000936:Antigen-Antibody Complex; D001483:Base Sequence; D002462:Cell Membrane / Q000276:immunology; D016764:Cell Polarity; D002478:Cells, Cultured; D004705:Endocytosis / Q000276:immunology*; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009895:Opsonin Proteins; D010587:Phagocytosis / Q000276:immunology*; D011487:Protein Conformation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014162:Transfection
D000936:Antigen-Antibody Complex; D008024:Ligands; D009895:Opsonin Proteins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D020794:Receptor Protein-Tyrosine Kinases