PMID- 10458769 OWN - NLM STAT- MEDLINE DCOM- 19990914 LR - 20180424 IS - 0014-2980 (Print) IS - 0014-2980 (Linking) VI - 29 IP - 8 DP - 1999 Aug TI - Dephosphorylation of ZAP-70 and inhibition of T cell activation by activated SHP1. PG - 2539-50 AB - 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 SHP1 in T lymphocytes, however, have remained unclear or controversial. To define these targets for SHP1 we have compared the effects of constitutively active and inactive mutants of SHP1 on TCR signaling. Expression of wild-type SHP1 had a very small effect on the TCR-induced tyrosine phosphorylation of ZAP-70 and Syk, even when SHP1 was overexpressed 20 - 100-fold over endogenous SHP1. Inactive SHP1-D421A and wild-type SHP2 were without effects. Constitutively active SHP1-DeltaSH2 had a more pronounced effect on ZAP-70 and Syk, even when expressed at near physiological levels. SHP1-DeltaSH2 also inhibited events downstream of ZAP-70 and Syk, such as activation of the mitogen-activated protein kinase Erk2 and the transcriptional activation of the interleukin-2 gene. In contrast, a constitutively active SHP2-DeltaSH2 had no statistically significant effect (although it caused a slight augmentation in some individual experiments). None of the constructs influenced the anti-CD3-induced tyrosine phosphorylation of the TCR zeta-chain or phospholipase Cgamma1, indicating that Src family kinase function was intact. Taken together, our findings support the notion that ZAP-70 and Syk can be direct substrates for SHP1 in intact cells. However, the two SH2 domains of SHP1 did not facilitate its recognition of ZAP-70 and Syk as substrates in intact cells. Therefore, we suggest that SHP1 is not actively recruited to inhibit TCR signaling induced by ligation of this receptor alone. Instead, we propose that ligation of a distinct inhibitory receptor leads to the recruitment of SHP1 via its SH2 domains, activation of SHP1 and subsequently inhibition of TCR signals if the inhibitory receptor is juxtaposed to the TCR. FAU - Brockdorff, J AU - Brockdorff J AD - La Jolla Institute for Allergy and Immunology, San Diego, California, USA. FAU - Williams, S AU - Williams S FAU - Couture, C AU - Couture C FAU - Mustelin, T AU - Mustelin T LA - eng GR - AI35603/AI/NIAID NIH HHS/United States GR - AI40552/AI/NIAID NIH HHS/United States GR - AI41481/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - Germany TA - Eur J Immunol JT - European journal of immunology JID - 1273201 RN - 0 (DNA-Binding Proteins) RN - 0 (Enzyme Precursors) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (NFATC Transcription Factors) RN - 0 (Nuclear Proteins) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Transcription Factor AP-1) RN - 0 (Transcription Factors) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (SYK protein, human) RN - EC 2.7.10.2 (Syk Kinase) RN - EC 2.7.10.2 (Syk protein, mouse) RN - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase) RN - EC 2.7.10.2 (ZAP70 protein, human) RN - EC 2.7.10.2 (Zap70 protein, mouse) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) RN - EC 3.1.3.48 (PTPN6 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases) RN - EC 3.1.3.48 (Ptpn6 protein, mouse) SB - IM MH - Animals MH - Calcium-Calmodulin-Dependent Protein Kinases/metabolism MH - DNA-Binding Proteins/metabolism MH - Enzyme Activation MH - Enzyme Precursors/metabolism MH - Humans MH - Intracellular Signaling Peptides and Proteins MH - Jurkat Cells MH - Mice MH - Mutation MH - NFATC Transcription Factors MH - *Nuclear Proteins MH - Phosphorylation MH - Protein Tyrosine Phosphatase, Non-Receptor Type 6 MH - Protein Tyrosine Phosphatases/deficiency/genetics/*metabolism MH - Protein-Tyrosine Kinases/*metabolism MH - Receptors, Antigen, T-Cell/metabolism MH - Sequence Deletion MH - Signal Transduction MH - Syk Kinase MH - T-Lymphocytes/*enzymology/*immunology MH - Transcription Factor AP-1/metabolism MH - Transcription Factors/metabolism MH - ZAP-70 Protein-Tyrosine Kinase MH - src Homology Domains EDAT- 1999/08/24 00:00 MHDA- 1999/08/24 00:01 CRDT- 1999/08/24 00:00 PHST- 1999/08/24 00:00 [pubmed] PHST- 1999/08/24 00:01 [medline] PHST- 1999/08/24 00:00 [entrez] AID - 10.1002/(SICI)1521-4141(199908)29:08<2539::AID-IMMU2539>3.0.CO;2-M [doi] PST - ppublish SO - Eur J Immunol. 1999 Aug;29(8):2539-50. doi: 10.1002/(SICI)1521-4141(199908)29:08<2539::AID-IMMU2539>3.0.CO;2-M.