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EMBO J. 2014 Sep 1;33(17):1928-40. doi: 10.15252/embj.201387404. Epub 2014 Jun 24.

Dok1 and Dok2 proteins regulate natural killer cell development and function.

Author information

1
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.
2
Aix-Marseille Université, Marseille, France Centre d'Immunologie de Marseille-Luminy INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
3
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.
4
Departments of Medicine and Pathology, Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
5
Department for Histology and Embryology, School of Medicine University of Rijeka, Rijeka, Croatia.
6
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.
7
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.

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.

KEYWORDS:

Dok molecules; adaptor proteins; cell signaling; cytokine production; natural killer cells

PMID:
24963146
PMCID:
PMC4195787
DOI:
10.15252/embj.201387404
[Indexed for MEDLINE]
Free PMC Article
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