MECHANISMS OF SIGNAL TRANSDUCTION
Inhibition of the Wnt Signaling Pathway by the PR61 Subunit of Protein Phosphatase 2A*

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Axin, a negative regulator of the Wnt signaling pathway, forms a complex with glycogen synthase kinase-3β (GSK-3β), β-catenin, adenomatous polyposis coli (APC) gene product, and Dvl, and it regulates GSK-3β-dependent phosphorylation in the complex and the stability of β-catenin. Using yeast two-hybrid screening, we found that regulatory subunits of protein phosphatase 2A, PR61β and -γ, interact with Axin. PR61β or -γ formed a complex with Axin in intact cells, and their interaction was direct. The binding site of PR61β on Axin was different from those of GSK-3β, β-catenin, APC, and Dvl. Although PR61β did not affect the stability of β-catenin, it inhibited Dvl- and β-catenin-dependent T cell factor activation in mammalian cells. Moreover, it suppressed β-catenin-induced axis formation and expression of siamois, a Wnt target gene, inXenopus embryos, suggesting that PR61β acts either at the level of β-catenin or downstream of it. Taken together with the previous observations that PR61 interacts with APC and functions upstream of β-catenin, these results demonstrate that PR61 regulates the Wnt signaling pathway at various steps.

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Published, JBC Papers in Press, April 10, 2001, DOI 10.1074/jbc.M100443200

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This work was supported by grants-in-aid for scientific research (B) and for scientific research on priority areas (C) from the Ministry of Education, Science, and Culture, Japan, by grants from the Yamanouchi Foundation for Research on Metabolic Disorders, and by Research Grant 99-23195 from the Princess Takamatsu Cancer Research Fund. The Leuven research group was further supported by the Geconcerteerde OnderzoeksActies of the Flemish Community, by the InterUniversitaire AttractiePool, and by the E.C. Biomed2 Cancer Research Program.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.

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To whom all correspondence should be addressed: Dept. of Biochemistry, Faculty of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Tel.: 81-82-257-5130; Fax: 81-82-257-5134; E-mail: [email protected].