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* Department of Immunology and Signal Transduction, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Science, and
Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan
Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a
key mediator in lymphocyte differentiation, proliferation, and
activation. We previously showed that B cell linker protein (BLNK) is a
physiological substrate of SHP-1 and that B cell receptor (BCR)-induced
activation of c-Jun NH2-terminal kinase (JNK) is
significantly enhanced in cells expressing a form of SHP-1 lacking
phosphatase activity (SHP-1-C/S). In this study, we confirmed that
SHP-1 also exerts negative regulatory effects on JNK activation in
splenic B cells. To further clarify the role of SHP-1 in B cells, we
examined how dephosphorylation of BLNK by SHP-1 affects downstream
signaling events. When a BLNK mutant (BLNK
N) lacking the
NH2-terminal region, which contains four tyrosine residues,
was introduced in SHP-1-C/S-expressing WEHI-231 cells, the enhanced JNK
activation was inhibited. Among candidate proteins likely to regulate
JNK activation through BLNK, Nck adaptor protein was found to associate
with tyrosine-phosphorylated BLNK and this association was more
pronounced in SHP-1-C/S-expressing cells. Furthermore, expression of
dominant-negative forms of Nck inhibited BCR-induced JNK activation.
Finally, BCR-induced apoptosis was suppressed in SHP-1-C/S-expressing
cells and coexpression of Nck SH2 mutants or a dominant-negative form
of SEK1 reversed this phenotype. Collectively, these results suggest
that SHP-1 acts on BLNK, modulating its association with Nck, which in
turn negatively regulates JNK activation but exerts a positive effect
on apoptosis.
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