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Non-T Cell Activation Linker Promotes Mast Cell Survival by Dampening the Recruitment of SHIP1 by Linker for Activation of T Cells¹

Karine Roget^*,, Marie Malissen^,,¶, Odile Malbec^*,, Bernard Malissen^,,¶ and Marc Daëron^2,*,

^* Institut Pasteur, Département d’Immunologie, Unité d’Allergologie Moléculaire et Cellulaire, Paris, France; Institut National de la Santé et de la Recherche Médicale (Inserm), Unité 760, Paris, France; Centre d’Immunologie de Marseille-Luminy, Université de la Méditerrannée, Marseille, France; Inserm, Unité 631, Marseille, France; and ^¶ Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6102, Marseille, France

The linker for activation of T cells (LAT) and the non-T cell activation linker (NTAL) are two transmembrane adapters which organize IgE receptor (FcRI) signaling complexes in mast cells. LAT positively regulates, whereas NTAL negatively regulates mast cell activation. We previously found that the four distal tyrosines of LAT can generate negative signals. We show here that two of these tyrosines provide two binding sites for SHIP1, that LAT recruits SHIP1 in vivo, and that SHIP1 recruitment is enhanced in NTAL-deficient cells. We show that NTAL negatively regulates mast cell activation by decreasing the recruitment, by LAT, of molecules involved in FcRI-dependent positive signaling. We show that NTAL also decreases the recruitment of SHIP1 by LAT, leading to an increased phosphorylation of the antiapoptotic molecule Akt, and positively regulates mast cell survival. We finally show that the positive effect of NTAL on Akt phosphorylation and mast cell survival requires LAT. Our data thus document the mechanisms by which LAT and NTAL can generate both positive and negative signals which differentially regulate mast cell activation and survival. They also provide molecular bases for the recruitment of SHIP1 in FcRI signaling complexes. SHIP1 is a major negative regulator of mast cell activation and, hence, of allergic reactions.

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 the Institut Pasteur, Institut National de la Santé et de la Recherche Médicale and the Fondation pour la Recherche Médicale (Program Défis de la Recherche en Allergologie). K.R. was financially supported by the Ministère de l’Education Nationale, de la Recherche et de la Technologie and by a Pasteur-Weizmann fellowship.

² Address correspondence and reprint requests to Dr. Marc Daëron, Unité d’Allergologie Moléculaire et Cellulaire, Département d’Immunologie, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France. E-mail address: daeron{at}pasteur.fr

³ Abbreviations used in this paper: LAT, linker for activation of T cells; NTAL, non-T cell activation linker; BMMC, bone marrow-derived mast cell; WT, wild type; PI(3,4,5)P3, phosphatidylinositol (3, 4, 5)-trisphosphate; SH2, Src homology 2; PLC, phospholipase C; PDK, phosphoinositide-dependent protein kinase.