Direct suppression of TCR-mediated activation of extracellular signal- regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine- specific phosphatase

Masatsugu Oh-Hora, Masato Ogata, Yoshiko Mori, Masaaki Adachi, Kohzoh Imai, Atsushi Kosugi, Toshiyuki Hamaoka

    Research output: Contribution to journalArticle

    36 Citations (Scopus)

    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 p38α, 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 aa41 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.

    Original languageEnglish
    Pages (from-to)1282-1288
    Number of pages7
    JournalJournal of Immunology
    Volume163
    Issue number3
    Publication statusPublished - Aug 1 1999

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

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