Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A.
Axin, a negative regulator of the Wnt signaling pathway, forms a complex with glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, adenomatous polyposis coli (APC) gene product, and Dvl, and it regulates GSK-3beta-dependent phosphorylation in the complex and the stability of beta-catenin. Using yeast two-hybrid screening, we found that regulatory subunits of protein phosphatase 2A, PR61beta and -gamma, interact with Axin. PR61beta or -gamma formed a complex with Axin in intact cells, and their interaction was direct. The binding site of PR61beta on Axin was different from those of GSK-3beta, beta-catenin, APC, and Dvl. Although PR61beta did not affect the stability of beta-catenin, it inhibited Dvl- and beta-catenin-dependent T cell factor activation in mammalian cells. Moreover, it suppressed beta-catenin-induced axis formation and expression of siamois, a Wnt target gene, in Xenopus embryos, suggesting that PR61beta acts either at the level of beta-catenin or downstream of it. Taken together with the previous observations that PR61 interacts with APC and functions upstream of beta-catenin, these results demonstrate that PR61 regulates the Wnt signaling pathway at various steps.
Yamamoto
H
H
Department of Biochemistry, Faculty of Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Hinoi
T
T
Michiue
T
T
Fukui
A
A
Usui
H
H
Janssens
V
V
Van Hoof
C
C
Goris
J
J
Asashima
M
M
Kikuchi
A
A
D000818:Animals; D060466:Axin Protein; D019556:COS Cells; D003598:Cytoskeletal Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054648:Protein Phosphatase 2; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D015534:Trans-Activators; D051153:Wnt Proteins; D014981:Xenopus; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D060466:Axin Protein; C495266:CTNNB1 protein, Xenopus; D003598:Cytoskeletal Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2