Journal
MOLECULAR IMMUNOLOGY
Volume 48, Issue 1-3, Pages 171-178Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2010.08.012
Keywords
Spleen tyrosine kinase (Syk); Lyn; RBL-2H3; IgE; Fc epsilon RI; R406; BAY61 3606; Degranulation
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Spleen tyrosine kinase (Syk) is a key regulatory factor in t he IgE-mediated allergic signal transduction pathway in mast cells and basophils Syk is phosphorylated on a number of tyrosines following the binding of IgE/allergen complexes to Fc epsilon RI receptors leading to initiation of inflammatory signaling via downstream enzymes and scaffolding proteins We examined the kinases responsible for the phosphorylation of key Syk tyrosines in rat RBL-2H3 basophilic cells and bone marrow-derived mast cells (BMMCs) The phosphorylation of Syk tyrosine 346 was completely bloc ked by the novel Src family kinase inhibitor BIRA766 suggesting this tyrosine is a pure substrate for Src family kinases This was supported by the findings that kinase-dead (KD) Syk was efficiently phosphorylated on this tyrosine and that a specific Syk inhibitor BAY61-3606 was without effect The phosphorylation of other Syk tyrosines 317 342 519 and 520 was reduced by Syk and Src family inhibitors suggesting a role for auto- and trans-phosphorylation Lyn was the predominant Src family kinase expressed and activated in RBL-2H3 cells meanwhile Lyn knockdown with a specific siRNA interfered with the phosphorylation of all Syk tyrosines and the Syk substrates SLP-76 and LAT Pharmacological inhibition of Syk completely blocked the degranulation of RBL-2H3 and BMMCs However Lyn knockdown sensitized RBL-2H3 cells to REM-induced degranulation We showed that whilst interference with Lyn expression disrupts Fc epsilon RI proximal signaling via Syk and its direct substrates including SLP-76 and LAT distal activation of downstream proteins including Erk is enhanced This study identifies the responsible kinases for the phosphorylation of key Syk tyrosines and the propagation of Fc epsilon RI receptor mediated signal transduction in allergic responses (C) 2010 Elsevier Ltd All rights reserved
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