title: A role for the ITAM signaling module in specifying cytokine-receptor functions.
abstract: Diverse cellular responses to external cues are controlled by a small number of signal-transduction pathways, but how the specificity of functional outcomes is achieved remains unclear. Here we describe a mechanism for signal integration based on the functional coupling of two distinct signaling pathways widely used in leukocytes: the ITAM pathway and the Jak-STAT pathway. Through the use of the receptor for interferon-γ (IFN-γR) and the ITAM adaptor Fcγ as an example, we found that IFN-γ modified responses of the phagocytic antibody receptor FcγRI (CD64) to specify cell-autonomous antimicrobial functions. Unexpectedly, we also found that in peritoneal macrophages, IFN-γR itself required tonic signaling from Fcγ through the kinase PI(3)K for the induction of a subset of IFN-γ-specific antimicrobial functions. Our findings may be generalizable to other ITAM and Jak-STAT signaling pathways and may help explain signal integration by those pathways.
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jelena S
authors.initials: JS
authors.lastname: Bezbradica
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Rosenstein
authors.affiliation: Amnis at EMD Millipore, Seattle, Washington, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: DeMarco
authors.affiliation: 1] Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Present address: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Brodsky
authors.affiliation: Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
mesh_terms: D000818:Animals; D058491:Bacterial Load; D002478:Cells, Cultured; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D061625:Immunoreceptor Tyrosine-Based Activation Motif / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008088:Listeriosis / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015202:Protein Engineering; D020239:Receptor Cross-Talk / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D000096743:Interferon gamma Receptor
chemical_list: D007141:Immunoglobulin Fc Fragments; D007371:Interferon-gamma; D053614:Janus Kinase 2; D052247:Nitric Oxide Synthase Type II; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017452:Receptors, IgG; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C496317:Nos2 protein, mouse; C507926:Jak2 protein, mouse