Aggregation of the human high affinity immunoglobulin G receptor (FcγRI) activates both tyrosine kinase and G protein-coupled phosphoinositide 3-kinase isoforms

Phosphoinositide 3-kinases (PI3-kinases) play an important role in the generation of lipid second messengers and the transduction of a myriad of biological responses. Distinct isoforms have been shown to be exclusively activated either by tyrosine kinase-coupled or G protein-coupled receptors. We show here, however, that certain nonclassical receptors can couple to both tyrosine kinase- and G protein-dependent isoforms of PI3-kinase: thus, aggregation of FcγRI, the human high affinity IgG receptor, on monocytes unusually leads to activation of both of these types of PI3-kinase. After aggregation of FcγRI, phosphatidylinositol 3,4,5-triphosphate (PIP(3)) levels rise rapidly in interferon γ-primed cells, reaching a peak within 30 sec. Moreover, and in contrast to the situation observed after stimulation of these cells with either insulin or ATP, which exclusively activate the tyrosine kinase- and G protein-coupled forms of PI3-kinase, respectively, PIP(3) levels remain elevated up to 15 min after receptor aggregation. We show here that although the initial peak results from transient activation of the p85-dependent p110 isoform of PI-3kinase, presumably through recruitment of tyrosine kinases by the γ chain, the later sustained rise of PIP(3) results from activation of the G protein βγ subunit-sensitive isoform, p110γ. This finding indicates that receptors lacking an intrinsic signaling motif, such as FcγRI, can recruit both tyrosine kinase and G protein-coupled intracellular signaling molecules and thereby initiate cellular responses.