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mová*
ka*
* Department of Signal Transduction,
Department of Micromorphology of Biopolymers, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, and
Center for Research in Diabetes, Metabolism and Nutrition, 3rd Medical Faculty, Charles University, Prague, Czech Republic
Engagement of the Fc
RI in mast cells and basophils leads to a rapid tyrosine phosphorylation of the transmembrane adaptors LAT (linker for activation of T cells) and NTAL (non-T cell activation linker, also called LAB or LAT2). NTAL regulates activation of mast cells by a mechanism, which is incompletely understood. Here we report properties of rat basophilic leukemia cells with enhanced or reduced NTAL expression. Overexpression of NTAL led to changes in cell morphology, enhanced formation of actin filaments and inhibition of the FcRI-induced tyrosine phosphorylation of the FcRI subunits, Syk kinase and LAT and all downstream activation events, including calcium and secretory responses. In contrast, reduced expression of NTAL had little effect on early FcRI-induced signaling events but inhibited calcium mobilization and secretory response. Calcium response was also repressed in Ag-activated cells defective in Grb2, a major target of phosphorylated NTAL. Unexpectedly, in cells stimulated with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+ ATPase, the amount of cellular NTAL directly correlated with the uptake of extracellular calcium even though no enhanced tyrosine phosphorylation of NTAL was observed. The combined data indicate that NTAL regulates FcRI-mediated signaling at multiple steps and by different mechanisms. At early stages NTAL interferes with tyrosine phosphorylation of several substrates and formation of signaling assemblies, whereas at later stages it regulates the activity of store-operated calcium channels through a distinct mechanism independent of enhanced NTAL tyrosine phosphorylation.
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1 This work was supported by projects 1M6837805001 (Center of Molecular and Cellular Immunology) and LC-545 from Ministry of Education, Youth and Sports of the Czech Republic; Grants 204/05/H023 and 301/06/0361 from the Grant Agency of the Czech Republic; Grants A5052310 and 1QS500520551 from the Grant Agency of the Academy of Sciences of the Czech Republic; and Institutional project AVOZ50520514. The research of P.D. and P.H. was supported, respectively, by an International Research Scholar’s award from Howard Hughes Medical Institute and Research goal MSM0021620814 from the 3rd Faculty of Medicine, Charles University, Prague.
2 Address correspondence and reprint requests to Dr. Petr Dráber, Department of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vide
ská 1083, Prague, Czech Republic. E-mail address: draberpe{at}biomed.cas.cz
3 Abbreviations used in this paper: LAT, linker for activation of T cells; PLC, phospholipase C; SH2, Src homology 2; NTAL, non-T cell activation linker; BMMC, bone marrow-derived mast cell; RBL, rat basophilic leukemia; SOC, store-operated Ca2+; BSS, buffered saline solution; NP-40, Nonidet P-40; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; [Ca2+]i, concentration of free intracellular Ca2+; PIP3, phosphatidylinositol 3,4,5-trisphosphate; TNP, trinitrophenyl.
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