Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase.
Leukocyte protein tyrosine phosphatase (LC-PTP)/hemopoietic PTP is a human cytoplasmic PTP that is predominantly expressed in the hemopoietic cells. Recently, it was reported that hemopoietic PTP inhibited TCR-mediated signal transduction. However, the precise mechanism of the inhibition was not identified. Here we report that extracellular signal-regulated kinase (ERK) is the ... direct target of LC-PTP. LC-PTP dephosphorylated ERK2 in vitro. Expression of wild-type LC-PTP in 293T cells suppressed the phosphorylation of ERK2 by a mutant MEK1, which was constitutively active regardless of upstream activation signals. No suppression of the phosphorylation was observed by LC-PTPCS, a catalytically inactive mutant. In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades. LC-PTP and LC-PTPCS made complexes with ERK1, ERK2, and p38alpha, but not with the gain-of-function sevenmaker ERK2 mutant (D321N). A small deletion (aa 1-46) in the N-terminal portion of LC-PTP or Arg to Ala substitutions at aa 41 and 42 resulted in the loss of ERK binding activity. These LC-PTP mutants revealed little inhibition of the ERK cascade activated by TCR cross-linking. On the other hand, the wild-type LC-PTP did not suppress the phosphorylation of sevenmaker ERK2 mutant. Thus, the complex formation of LC-PTP with ERK is the essential mechanism for the suppression. Taken collectively, these results indicate that LC-PTP suppresses mitogen-activated protein kinase directly in vivo.
Mesh Terms:
Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Enzyme Activation, Genetic Vectors, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Kidney, MAP Kinase Kinase 1, Macromolecular Substances, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein Tyrosine Phosphatases, Non-Receptor, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Transfection, Tyrosine, p38 Mitogen-Activated Protein Kinases
Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Enzyme Activation, Genetic Vectors, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Kidney, MAP Kinase Kinase 1, Macromolecular Substances, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein Tyrosine Phosphatases, Non-Receptor, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Transfection, Tyrosine, p38 Mitogen-Activated Protein Kinases
J. Immunol.
Date: Aug. 01, 1999
PubMed ID: 10415025
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