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J Biol Chem, Vol. 274, Issue 16, 10681-10684, April 16, 1999
Regulates Its Stability
,
§,
,
,
From the Axin forms a complex with glycogen synthase
kinase-3
Department of Biochemistry, Hiroshima
University School of Medicine, 1-2-3, Kasumi, Minami-ku, Hiroshima
734-8551, Japan, § PRESTO, Japan Science and Technology
Corporation, Hiroshima 734-8551, Japan, and the ¶ Center for
Molecular and Developmental Biology, Faculty of Science, Kyoto
University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan
(GSK-3
) and
-catenin and promotes
GSK-3
-dependent phosphorylation of
-catenin, thereby
stimulating the degradation of
-catenin. Because GSK-3
also
phosphorylates Axin in the complex, the physiological significance of
the phosphorylation of Axin was examined. Treatment of COS cells with
LiCl, a GSK-3
inhibitor, and okadaic acid, a protein phosphatase
inhibitor, decreased and increased, respectively, the cellular protein
level of Axin. Pulse-chase analyses showed that the phosphorylated form
of Axin was more stable than the unphosphorylated form and that an Axin
mutant, in which the possible phosphorylation sites for GSK-3
were
mutated, exhibited a shorter half-life than wild type Axin. Dvl-1,
which was genetically shown to function upstream of GSK-3
, inhibited
the phosphorylation of Axin by GSK-3
in vitro.
Furthermore, Wnt-3a-containing conditioned medium down-regulated Axin
and accumulated
-catenin in L cells and expression of
Dvl-1
PDZ, in which the PDZ domain was deleted,
suppressed this action of Wnt-3a. These results suggest that the
phosphorylation of Axin is important for the regulation of its
stability and that Wnt down-regulates Axin through Dvl.
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