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J. Biol. Chem., Vol. 276, Issue 18, 14784-14790, May 4, 2001
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From the Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
The c-Jun N-terminal kinases (JNKs) are members
of the mitogen-activated protein kinase (MAPK) gene family and are
essential for cell proliferation, differentiation, and apoptosis.
Previously we found that activation of JNK in T-cells required
costimulation of both T-cell receptor and auxiliary receptors
such as CD28. In this study, we cloned a full-length human MEK kinase
(MEKK) 2 cDNA from Jurkat T-cells and demonstrated that it was a
major upstream MAPK kinase kinase for the JNK cascade in T-cells. The human MEKK2 cDNA encoded a polypeptide of 619 amino acids and was
the human counterpart of the reported murine MEKK2. It was 94%
homologous with human and murine MEKK3 at the catalytic domains and
60% homologous at the N-terminal noncatalytic region. Northern blot
analysis showed that MEKK2 was ubiquitously expressed, with the highest
level in peripheral blood leukocytes. In T cells, MEKK2 was found to be
a strong activator of JNK but not of extracellular signal-regulated
kinase MAPKs and to activate JNK-dependent AP-1 reporter
gene expression. MEKK2 also synergized with anti-CD3 antibody to
activate JNK in T cells, and stimulation of T cells led to induction of
MEKK2 tyrosine phosphorylation. Significantly, the JNK activation
induced by anti-CD3 and anti-CD28 antibodies, but not by
12-O-tetradecanoylphorbol-13-acetate and Ca2+
ionophore A23187, was inhibited by dominant negative MEKK2 mutants. AP-1 and interleukin-2 reporter gene induction in T-cells was also
inhibited by dominant negative MEKK2 mutants. Taken together, our
results showed that human MEKK2 is a key signaling molecule for T-cell
receptor/CD3-mediated JNK MAPK activation and interleukin-2 gene expression.
MEKK2 Is Required for T-cell Receptor Signals in JNK Activation
and Interleukin-2 Gene Expression*
,
*
This work was supported in part by National Institutes of
Health Grant RO1(AI44016) and American Cancer Society Grant RPG97-090 (to B. S.) and Cancer Center Support Grant CA16672 (to M. D. Anderson Cancer Center).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
A special fellow of the Leukemia Society of America. To whom
correspondence should be addressed: Dept. of Immunology, Box 178, The
University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd.,
Houston, TX 77030. Tel.: 713-792-8742; Fax: 713-745-1633; E-mail:
bingsu@odin.mdacc.tmc.edu.
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