Abstract
Src homology region 2 domain-containing phosphatase 1 (SHP-1), a cytoplasmic protein tyrosine phosphatase, plays an important role for the regulation of signaling from various hematopoietic cell receptors. Although SHP-1 is shown to be a negative signal modulator in mast cells, its precise molecular mechanisms are not well defined. To elucidate how SHP-1 regulates mast cell signaling, we established bone marrow-derived mast cells from SHP-1-deficient motheaten and wild-type mice and analyzed downstream signals induced by cross-linking of high affinity IgE receptor, Fc epsilonRI. Upon Fc epsilonRI ligation, motheaten-derived bone marrow-derived mast cells showed enhanced tyrosine phosphorylation of Src homology region 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and linker for activation of T cells, activation of mitogen-activated protein kinases and gene transcription and production of cytokine. Because the activity of Syk, responsible for the phosphorylation of SLP-76 and linker for activation of T cells, is comparable irrespective of SHP-1, both molecules might be substrates of SHP-1 in mast cells. Interestingly, the absence of SHP-1 expression disrupted the association between SLP-76 and phospholipase Cgamma, which resulted in the decreased phospholipase Cgamma phosphorylation, calcium mobilization, and degranulation. Collectively, these results suggest that SHP-1 regulates Fc epsilonRI-induced downstream signaling events both negatively and positively by functioning as a protein tyrosine phosphatase and as an adaptor protein contributing to the formation of signaling complex, respectively.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Calcium / immunology
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Calcium / metabolism
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Cell Degranulation / genetics
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Cell Degranulation / immunology*
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Extracellular Signal-Regulated MAP Kinases
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Gene Expression Regulation, Enzymologic / genetics
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Gene Expression Regulation, Enzymologic / immunology*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Intracellular Signaling Peptides and Proteins / metabolism
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Mast Cells / enzymology
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Mast Cells / immunology*
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Mice
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Mice, Mutant Strains
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Phospholipase C gamma / genetics
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Phospholipase C gamma / immunology
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Phosphoproteins / genetics
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Phosphoproteins / immunology
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism
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Receptors, IgE / genetics
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Receptors, IgE / immunology*
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Receptors, IgE / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Syk Kinase
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Receptors, IgE
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SLP-76 signal Transducing adaptor proteins
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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Extracellular Signal-Regulated MAP Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, mouse
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Phospholipase C gamma
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Calcium