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PMID:10415025

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Citation

Oh-hora, M, Ogata, M, Mori, Y, Adachi, M, Imai, K, Kosugi, A and Hamaoka, T (1999) Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. J. Immunol. 163:1282-8

Abstract

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.

Links

PubMed

Keywords

Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Cell Line; Enzyme Activation/immunology; Genetic Vectors/metabolism; 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/immunology; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases/genetics; Protein Tyrosine Phosphatases/physiology; Protein Tyrosine Phosphatases, Non-Receptor; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Protein-Tyrosine Kinases/genetics; Protein-Tyrosine Kinases/metabolism; Receptors, Antigen, T-Cell/physiology; Recombinant Fusion Proteins/biosynthesis; Recombinant Fusion Proteins/metabolism; Transfection; Tyrosine/metabolism; p38 Mitogen-Activated Protein Kinases

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MK01

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35236

F

Seeded From UniProt

complete

HUMAN:PTN7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P28482

F

Seeded From UniProt

complete

HUMAN:PTN7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P47811

F

Seeded From UniProt

complete

MOUSE:MK14

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35236

F

Seeded From UniProt

complete

Notes

See also

References

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