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Cutting Edge: Dok-1 and Dok-2 Adaptor Molecules Are Regulated by Phosphatidylinositol 5-Phosphate Production in T Cells¹

Geoffrey Guittard^2,*,,, Audrey Gérard^2,*,,, Sophie Dupuis-Coronas, Hélène Tronchère, Eva Mortier^¶, Cédric Favre^*,,, Daniel Olive^*,,, Pascale Zimmermann^¶, Bernard Payrastre and Jacques A. Nunès^3,*,,

^* Institut National de la Santé et de la Recherche Médicale, Unité 891, Centre de Recherche en Cancérologie de Marseille, Marseille, France; Institut Paoli-Calmettes, Marseille, France; Université Méditerranée, Marseille, France; Institut National de la Santé et de la Recherche Médicale, Unité 563, Centre de Physiopathologie Toulouse Purpan, Département d’Oncogenèse, Signalisation et Innovation Thérapeutique; Université Toulouse III Paul Sabatier and Centre Hospitalier Universitaire de Toulouse, Toulouse, France; and ^¶ Laboratory for Signal Integration in Cell Fate Decision, Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

Downstream of tyrosine kinase (Dok) proteins Dok-1 and Dok-2 are involved in T cell homeostasis maintenance. Dok protein tyrosine phosphorylation plays a key role in establishing negative feedback loops of T cell signaling. These structurally related adapter molecules contain a pleckstrin homology (PH) domain generally acting as a lipid/protein-interacting module. We show that the presence of this PH domain is necessary for the tyrosine phosphorylation of Dok proteins and their negative functions in T cells. We find that Dok-1/Dok-2 PH domains bind in vitro to the rare phosphoinositide species, phosphatidylinositol 5-phosphate (PtdIns5P). Dok tyrosine phosphorylation correlates with PtdIns5P production in T cells upon TCR triggering. Furthermore, we demonstrate that PtdIns5P increase regulates Dok tyrosine phosphorylation in vivo. Together, our data identify a novel lipid mediator in T cell signaling and suggest that PH-PtdIns5P interactions regulate T cell responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, the Institut National du Cancer (PL-06026), the Association pour la Recherche sur le Cancer (4202), Agence Nationale de Recherches Programme Blanc (0065-01), the Fund for Scientific Research-Flanders, the Belgian Federation against Cancer, the Concerted Actions Program, and the Research Fund of the Katholieke Universiteit Leuven. G.G. was supported by fellowship from the Institut National de la Santé et de la Recherche Médicale/Région Provence-Alpes Côte d’Azur, and the Ligue Nationale Contre le Cancer. A.G. was supported by fellowship from the Ligue Nationale Contre le Cancer.

² G.G. and A.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jacques A. Nunès, Centre de Recherche en Cancérologie de Marseille, 27 Boulevard Lei Roure, 13009 Marseille, France. E-mail address: jacques.nunes{at}inserm.fr

⁴ Abbreviations used in this paper: PTK protein tyrosine kinase; Dok, downstream of tyrosine kinase; HA, hemagglutinin; PH, pleckstrin homology; PHD, plant homeodomain; PI, phosphoinositide; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,4,5)P₃, phosphatidylinositol 3,4,5-trisphosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; PtdIns5P, phosphatidylinositol 5-phosphate; SPR, surface plasmon resonance.

⁵ The online version of this article contains supplemental material.