Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation.
The 21-kDa dual specific protein phosphatase VH1-related (VHR) is one of the smallest known phosphatases, and its function has remained obscure. We report that this enzyme is expressed in lymphoid cells and is not induced by T cell antigen receptor like other dual specificity phosphatases. Introduction of exogenous VHR into Jurkat T cells caused a marked decrease in the transcriptional activation of a nuclear factor of activated T cells and an activator protein-1-driven reporter gene in response to ligation of T cell antigen receptors. The inhibition was dose-dependent and was similar at different doses of anti-receptor antibody. Catalytically inactive VHR mutants caused an increase in gene activation, suggesting a role for endogenous VHR in this response. In contrast, the activation of a nuclear factor kappaB-driven reporter was not affected. The inhibitory effects of VHR were also seen at the level of the mitogen-activated kinases Erk1, Erk2, Jnk1, Jnk2, and on reporter genes that directly depend on these kinases, namely Elk, c-Jun, and activator protein-1. In contrast, p38 kinase activation was not affected by VHR, and p38-assisted gene activation was less sensitive. Our results suggest that VHR is a negative regulator of the Erk and Jnk pathways in T cells and, therefore, may play a role in aspects of T lymphocyte physiology that depend on these kinases.
Alonso
A
A
Laboratory of Signal Transduction, La Jolla Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.
Saxena
M
M
Williams
S
S
Mustelin
T
T
D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D054640:Dual Specificity Phosphatase 3; D004789:Enzyme Activation; D017930:Genes, Reporter; D018882:Heat Stress Disorders; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays
D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; D017027:Protein Tyrosine Phosphatases