PTPα Activates Lyn and Fyn and Suppresses Hck to Negatively Regulate FcεRI-Dependent Mast Cell Activation and Allergic Responses
| Autor: | Catherine J. Pallen, Lionel A. Samayawardhena |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Immunology Syk Protein tyrosine phosphatase Proto-Oncogene Proteins c-fyn environment and public health Cell Degranulation Mice FYN LYN Hypersensitivity Animals Immunology and Allergy Mast Cells Mice Knockout Tyrosine-protein kinase CSK Receptors IgE Chemistry Kinase Receptor-Like Protein Tyrosine Phosphatases Class 4 hemic and immune systems Mice Inbred C57BL enzymes and coenzymes (carbohydrates) src-Family Kinases Proto-Oncogene Proteins c-hck Cancer research Phosphorylation Signal Transduction |
| Zdroj: | The Journal of Immunology. 185:5993-6002 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1001261 |
| Popis: | Mast cell activation via FcεRI involves activation of the Src family kinases (SFKs) Lyn, Fyn, and Hck that positively or, in the case of Lyn, negatively regulate cellular responses. Little is known of upstream activators of these SFKs in FcεRI-dependent signaling. We investigated the role of receptor protein tyrosine phosphatase (PTP)α, a well-known activator of SFKs in diverse signaling systems, FcεRI-mediated mast cell activation, and IgE-dependent allergic responses in mice. PTPα−/− bone marrow-derived mast cells hyperdegranulate and exhibit increased cytokine and cysteinyl leukotriene secretion, and PTPα−/− mice display enhanced IgE-dependent anaphylaxis. At or proximal to FcεRI, PTPα−/− cells have reduced IgE-dependent activation of Lyn and Fyn, as well as reduced FcεRI and SHIP phosphorylation. In contrast, Hck and Syk activation is enhanced. Syk hyperactivation correlated with its increased phosphorylation at positive regulatory sites and defective phosphorylation at a negative regulatory site. Distal to FcεRI, we observed increased activation of PI3K and MAPK pathways. These findings demonstrate that PTPα activates the FcεRI-coupled kinases Lyn and Fyn and suppresses Hck activity. Furthermore, the findings indicate that hyperactivation of PTPα−/− mast cells and enhanced IgE-dependent allergic responses of PTPα−/− mice are due to the ablated function of PTPα as a critical regulator of Lyn negative signaling. |
| Databáze: | OpenAIRE |
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