Positive regulation of c-Jun N-terminal kinase and TNF-alpha production but not histamine release by SHP-1 in RBL-2H3 mast cells.
The SH2-containing protein tyrosine phosphatase1 (SHP-1) is important for signaling from immune receptors. To investigate the role of SHP-1 in mast cells we overexpressed the wild-type and the phosphatase-inactive forms of SHP-1 in rat basophilic leukemia 2H3 (RBL-2H3) mast cell line. The phosphatase-inactive SHP-1 (C453S or D419A) retains its ability to bind tyrosine phosphorylated substrates and thereby competes with the endogenous wild-type enzyme. Overexpression of wild-type SHP-1 decreased the FcepsilonRI aggregation-induced tyrosine phosphorylation of the beta and gamma subunits of the receptor whereas the dominant negative SHP-1 enhanced phosphorylation. There were also similar changes in the tyrosine phosphorylation of Syk. However, receptor-induced histamine release in the cells expressing either wild-type or dominant negative SHP-1 was similar to that in the parental control cells. In contrast, compared with the parental RBL-2H3 cells, FcepsilonRI-induced c-Jun N-terminal kinase phosphorylation and the level of TNF-alpha mRNA was increased in the cells overexpressing wild-type SHP-1 whereas the dominant negative SHP-1 had the opposite effect. The substrate-trapping mutant SHP1/D419A identified pp25 and pp30 as two major potential substrates of SHP-1 in RBL-2H3 cells. Therefore, SHP-1 may play a role in allergy and inflammation by regulating mast cell cytokine production.
Xie
Z H
ZH
Receptors and Signal Transduction Section, OIIB, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. zxie@dir.nidr.nih.gov
Zhang
J
J
Siraganian
R P
RP
D000818:Animals; D000941:Antigens / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004792:Enzyme Precursors / Q000378:metabolism; D006636:Histamine Release / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D008970:Molecular Weight; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism / Q000502:physiology; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D013379:Substrate Specificity; D000072377:Syk Kinase; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology*
D000941:Antigens; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases