title: Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses.
abstract: Plasmacytoid dendritic cells (pDC) are type I interferon-producing cells with critical functions in a number of human illnesses; however, their molecular regulation is incompletely understood. Here we show the role of Src family kinases (SFK) in mouse and human pDCs. pDCs express Fyn and Lyn and their activating residues are phosphorylated both before and after Toll-like receptor (TLR) stimulation. Fyn or Lyn genetic ablation as well as treatment with SFK inhibitors ablate pDC (but not conventional DC) responses both in vitro and in vivo. Inhibition of SFK activity not only alters TLR-ligand localization and inhibits downstream signalling events, but, independent of ex-vivo TLR stimulation, also affects constitutive phosphorylation of BCAP, an adaptor protein bridging PI3K and TLR pathways. Our data identify Fyn and Lyn as important factors that promote pDC responses, describe the mechanisms involved and highlight a tonic SFK-mediated signalling that precedes pathogen encounter, raising the possibility that small molecules targeting SFKs could modulate pDC responses in human diseases.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dallari
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: M
authors.initials: M
authors.lastname: Macal
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Loureiro
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jo
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: L
authors.initials: L
authors.lastname: Swanson
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hesser
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California, 9500 Gilman Dr La Jolla, San Diego, California 92093, USA.
authors.forename: E I
authors.initials: EI
authors.lastname: Zuniga
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003586:Cytomegalovirus Infections / Q000473:pathology / Q000821:virology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D008024:Ligands; C520779:ODF2L protein, human; D011743:Pyrimidines; D051193:Toll-Like Receptors; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases; C506918:bafetinib