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 phosphatase(1) (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 phosphat ase-inactive SHP-1 (C453S or D419A) retains its ability to bind tyrosine ph osphorylated substrates and thereby competes with the endogenous wild-type enzyme. Overexpression of wild-type SHP-1 decreased the Fc epsilon RI aggre gation-induced tyrosine phosphorylation of the beta and gamma subunits of t he receptor whereas the dominant negative SHP-1 enhanced phosphorylation. T here were also similar changes in the tyrosine phosphorylation of Syk. Howe ver, receptor-induced histamine release in the cells expressing either wild -type or dominant negative SHP-1 was similar to that in the parental contro l cells. In contrast, compared with the parental RBL-2H3 cells, Fc epsilon RI-induced c-Jun N-terminal kinase phosphorylation and the level of TNF-alp ha mRNA was increased in the cells overexpressing wild-type SHP-1 whereas t he dominant negative SHP-1 had the opposite effect. The substrate-trapping mutant SHP1/D419A identified pp25 and pp30 as two major potential substrate s of SHP-1 in RBL-2H3 cells. Therefore, SHP-1 may play a role in allergy an d inflammation by regulating mast cell cytokine production.