title: Dok1 and Dok2 proteins regulate natural killer cell development and function.
abstract: Natural killer (NK) cells are involved in immune responses against tumors and microbes. NK-cell activation is regulated by intrinsic and extrinsic mechanisms that ensure NK tolerance and efficacy. Here, we show that the cytoplasmic signaling molecules Dok1 and Dok2 are tyrosine phosphorylated upon NK-cell activation. Overexpression of Dok proteins in human NK cells reduces cell activation induced by NK-cell-activating receptors. Dok1 and Dok2 gene ablation in mice induces an NK-cell maturation defect and leads to increased IFN-γ production induced by activating receptors. Taken together, these results reveal that Dok1 and Dok2 proteins are involved in an intrinsic negative feedback loop downstream of NK-cell-activating receptors in mouse and human.
authors: INSERM U1068 Centre de Recherche en Cancérologie de Marseille, Marseille, France Institut Paoli-Calmettes, Marseille, France CNRS UMR7258 Centre de Recherche en Cancérologie de Marseille, Marseille, France Aix-Marseille Université, Marseille, France.
authors: Javier
authors: J
authors: Celis-Gutierrez
authors: Aix-Marseille Université, Marseille, France Centre d'Immunologie de Marseille-Luminy INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors: Marilyn
authors: M
authors: Boyron
authors: Aix-Marseille Université, Marseille, France Centre d'Immunologie de Marseille-Luminy INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France Université de Lyon INSERM U1111, Lyon, France.
authors: Thierry
authors: T
authors: Walzer
authors: Departments of Medicine and Pathology, Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Department for Histology and Embryology, School of Medicine University of Rijeka, Rijeka, Croatia.
authors: Stipan
authors: S
authors: Jonjić
authors: INSERM U1068 Centre de Recherche en Cancérologie de Marseille, Marseille, France Institut Paoli-Calmettes, Marseille, France CNRS UMR7258 Centre de Recherche en Cancérologie de Marseille, Marseille, France Aix-Marseille Université, Marseille, France.
authors: Daniel
authors: D
authors: Olive
authors: Aix-Marseille Université, Marseille, France Centre d'Immunologie de Marseille-Luminy INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors: Marc
authors: M
authors: Dalod
authors: Aix-Marseille Université, Marseille, France Centre d'Immunologie de Marseille-Luminy INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France Service d'Immunologie, Assistance Publique - Hôpitaux de Marseille Hôpital de la Conception, Marseille, France.
authors: Eric
authors: E
authors: Vivier
authors: INSERM U1068 Centre de Recherche en Cancérologie de Marseille, Marseille, France Institut Paoli-Calmettes, Marseille, France CNRS UMR7258 Centre de Recherche en Cancérologie de Marseille, Marseille, France Aix-Marseille Université, Marseille, France jacques.nunes@inserm.fr.
authors: Jacques A
authors: JA
authors: Nunès
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C115089:DOK2 protein, human; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D007371:Interferon-gamma
keywords: Dok molecules; adaptor proteins; cell signaling; cytokine production; natural killer cells