Aggregation of the human high affinity immunoglobulin G receptor (FcgammaRI) 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 FcgammaRI, the human high affinity IgG receptor, on monocytes unusually leads to activation of both of these types of PI3-kinase. After aggregation of FcgammaRI, phosphatidylinositol 3,4, 5-triphosphate (PIP3) levels rise rapidly in interferon gamma-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, PIP3 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 gamma chain, the later sustained rise of PIP3 results from activation of the G protein betagamma subunit-sensitive isoform, p110gamma. This finding indicates that receptors lacking an intrinsic signaling motif, such as FcgammaRI, can recruit both tyrosine kinase and G protein-coupled intracellular signaling molecules and thereby initiate cellular responses.
Melendez
A J
AJ
Department of Medicine and Therapeutics and Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
Gillooly
D J
DJ
Harnett
M M
MM
Allen
J M
JM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D009687:Nuclear Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016601:RNA-Binding Proteins; D017452:Receptors, IgG / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D000068103:Serine-Arginine Splicing Factors
D007328:Insulin; D007527:Isoenzymes; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D017452:Receptors, IgG; C060974:phosphatidylinositol 3,4,5-triphosphate; D000068103:Serine-Arginine Splicing Factors; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases