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*
Biomedical Research Center, Osaka University Medical School, Osaka, Japan;
Department of Internal Medicine, Sapporo Medical School of Medicine, Sapporo, Japan; and
School of Allied Health Science, Faculty of Medicine, Osaka University, Osaka, Japan
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 p38
, 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.
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