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Petra Volná¹, Pavel Lebduka¹, Lubica Dráberová¹, árka ímová¹, Petr Heneberg¹, Michael Boubelík¹, Viktor Bugajev¹, Bernard Malissen², Bridget S. Wilson³, Václav Hoejí¹, Marie Malissen², and Petr Dráber¹

¹ Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic
² Centre d'Immunologie de Marseille-Luminy, INSERM–CNRS–Université de la Méditerranée, 13288 Marseille Cedex 9, France
³ Department of Pathology and Cancer Research, University of New Mexico Health Sciences Center, Albuquerque, NM 87131

Address correspondence to Petr Dráber, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeská 1083, 142 20 Prague 4, Czech Republic. Phone: 420-241-062-468; Fax: 420-241-470-339; email: draberpe{at}biomed.cas.cz; or Marie Malissen, Centre d'Immunologie de Marseille-Luminy, INSERM–CNRS–Univ. Med., Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France. Phone: 33-491269402; Fax: 33-491269430; email: malissen{at}ciml.univ-mrs.fr

Engagement of the Fc receptor I (FcRI) on mast cells and basophils initiates signaling pathways leading to degranulation. Early activation events include tyrosine phosphorylation of two transmembrane adaptor proteins, linker for activation of T cells (LAT) and non–T cell activation linker (NTAL; also called LAB; a product of Wbscr5 gene). Previous studies showed that the secretory response was partially inhibited in bone marrow–derived mast cells (BMMCs) from LAT-deficient mice. To clarify the role of NTAL in mast cell degranulation, we compared FcRI-mediated signaling events in BMMCs from NTAL-deficient and wild-type mice. Although NTAL is structurally similar to LAT, antigen-mediated degranulation responses were unexpectedly increased in NTAL-deficient mast cells. The earliest event affected was enhanced tyrosine phosphorylation of LAT in antigen-activated cells. This was accompanied by enhanced tyrosine phosphorylation and enzymatic activity of phospholipase C 1 and phospholipase C 2, resulting in elevated levels of inositol 1,4,5-trisphosphate and free intracellular Ca²⁺. NTAL-deficient BMMCs also exhibited an enhanced activity of phosphatidylinositol 3-OH kinase and Src homology 2 domain–containing protein tyrosine phosphatase-2. Although both LAT and NTAL are considered to be localized in membrane rafts, immunogold electron microscopy on isolated membrane sheets demonstrated their independent clustering. The combined data show that NTAL is functionally and topographically different from LAT.

Key Words: mast cell • signal transduction • Fc receptor • calcium mobilization • adapter molecules

Abbreviations used in this paper: Ag, antigen; BMMC, BM-derived mast cell; BSS, buffered saline solution; [Ca²⁺]_i, concentration of free intracellular calcium; ES, embryonic stem; FcRI, Fc receptor I; HRP, horseradish peroxidase; IP3, inositol 1,4,5-trisphosphate; LAT, linker for activation of T cells; MAP, mitogen-activated protein; NTAL, non–T cell activation linker; PI, phosphatidylinositol; PI3K, PI 3-OH kinase; PLC, phospholipase C; PS, phosphatidylserine; SCF, stem cell factor; SH, Src homology.

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