Positive and negative regulation of high affinity IgE receptor signaling by Src homology region 2 domain-containing phosphatase 1.
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.
Nakata
Kazuko
K
Department of Immunology and Signal Transduction, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Science, Fuchu, Tokyo, Japan.
Yoshimaru
Tetsuro
T
Suzuki
Yoshihiro
Y
Inoue
Toshio
T
Ra
Chisei
C
Yakura
Hidetaka
H
Mizuno
Kazuya
K
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; C092947:SLP-76 signal Transducing adaptor proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D051966:Phospholipase C gamma; D002118:Calcium