Dephosphorylation of ZAP-70 and inhibition of T cell activation by activated SHP1.

摘要: Studies with motheaten mice, which lack the SHP1 protein tyrosine phosphatase, indicate that this enzyme plays an important negative role in T cell antigen receptor (TCR) signaling. The physiological substrates for lymphocytes, however, have remained unclear or controversial. To define these targets we compared effects of constitutively active and inactive mutants on TCR Expression wild-type had a very small effect TCR-induced phosphorylation ZAP-70 Syk, even when was overexpressed 20 - 100-fold over endogenous SHP1. Inactive SHP1-D421A SHP2 were without effects. Constitutively SHP1-DeltaSH2 more pronounced expressed at near levels. also inhibited events downstream such as activation mitogen-activated kinase Erk2 transcriptional interleukin-2 gene. In contrast, SHP2-DeltaSH2 no statistically significant (although it caused slight augmentation some individual experiments). None constructs influenced anti-CD3-induced zeta-chain phospholipase Cgamma1, indicating Src family function intact. Taken together, our findings support notion Syk can be direct intact cells. However, two SH2 domains did not facilitate its recognition Therefore, suggest is actively recruited to inhibit signaling induced by ligation alone. Instead, propose distinct inhibitory leads recruitment via domains, subsequently inhibition signals if juxtaposed TCR.