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PDBsum entry 4uy9
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References listed in PDB file
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Key reference
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Title
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Recurrent mlk4 loss-Of-Function mutations suppress jnk signaling to promote colon tumorigenesis.
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Authors
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A.A.Marusiak,
N.L.Stephenson,
H.Baik,
E.W.Trotter,
Y.Li,
K.Blyth,
S.Mason,
P.Chapman,
L.A.Puto,
J.A.Read,
C.Brassington,
H.K.Pollard,
C.Phillips,
I.Green,
R.Overman,
M.Collier,
E.Testoni,
C.J.Miller,
T.Hunter,
O.J.Sansom,
J.Brognard.
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Ref.
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Cancer Res, 2016,
76,
724-735.
[DOI no: ]
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PubMed id
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Abstract
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MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK,
p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in
various human cancers, including frequently in colorectal cancer, where their
function and pathobiological importance have been uncertain. In this study, we
assessed the functional consequences of MLK4 mutations in colon tumorigenesis.
Biochemical data indicated that a majority of MLK4 mutations are
loss-of-function (LOF) mutations that can exert dominant-negative effects. In
seeking to understand the abrogated activity of these mutants, we elucidated a
new MLK4 catalytic domain structure. To determine whether MLK4 is required to
maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon
cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4
activity reduced cell viability, proliferation, and colony formation in vitro
and delayed tumor growth in vivo. Mechanistic investigations established that
restoring the function of MLK4 selectively induced the JNK pathway and its
downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors
CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing
kinase harboring frequent LOF mutations that lead to diminished signaling in the
JNK pathway and enhanced proliferation in colon cancer. Cancer Res; 76(3);
724-35. ©2015 AACR.
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