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Protein Tyrosine Phosphatase ε is a Negative Regulator of FcεRI‐mediated Mast Cell Responses
Author(s) -
Akimoto M.,
Mishra K.,
Lim K.T.,
Tani N.,
Hisanaga S.i.,
Katagiri T.,
Elson A.,
Mizuno K.,
Yakura H.
Publication year - 2009
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2009.02235.x
Subject(s) - degranulation , syk , lyn , fyn , protein tyrosine phosphatase , mast cell , microbiology and biotechnology , phosphorylation , tyrosine phosphorylation , immunoglobulin e , proto oncogene tyrosine protein kinase src , chemistry , kinase , tyrosine kinase , signal transduction , biology , receptor , immunology , biochemistry , antibody
Modulation of mast‐cell activation may provide novel ways to control allergic diseases. Here, we show that protein tyrosine phosphatase ε (PTPε; Ptpre ) plays key regulatory roles during mast‐cell activation mediated by the high‐affinity IgE receptor (FcεRI). Bone marrow‐derived mast cells (BMMC) from Ptpre −/− mice exhibited enhanced FcεRI‐induced Ca 2+ mobilization and mitogen‐activated protein kinase (MAPK) (JNK and p38) activation, and showed corresponding enhancement of evoked degranulation and cytokine production, but not leukotriene production. Examination of proteins linking tyrosine kinase activation and Ca 2+ mobilization revealed that the absence of PTPε leads to increased phosphorylation of the linker for activation of T cells and SH2 domain‐containing leucocyte phosphoproteins of 76 kDa, but not Grb2‐associated binder‐2 (Gab2). Because Gab2 is considered to be situated downstream of Fyn kinase, we reasoned that Fyn may not be a target of PTPε. In the event, Syk but not Lyn was hyperphosphorylated in PTPε‐deficient BMMC. Thus, PTPε most likely exerts its effects at the level of Syk, inhibiting downstream events including phosphorylation of SLP‐76 and linker of activated T cells and mobilization of Ca 2+ . Consistent with the in vitro data, antigen‐ and IgE‐mediated passive systemic anaphylactic reactions were augmented in Ptpre −/− mice. Given that the number of mast cells is unchanged in these mice, this observation most likely reflects alterations of mast cell‐autonomous signalling events. These data suggest that PTPε negatively regulates FcεRI‐mediated signalling pathways and thus constitutes a novel target for ameliorating allergic conditions.