Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus

• Published in: The EMBO journal Vol. 20; no. 15; pp. 4122 - 4131
• Main Authors: Li, Xinghai, Yost, H.Joseph, Virshup, David M., Seeling, Joni M.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-08-2001; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Animals; Antigens, Viral, Tumor - metabolism; axin; Axin Protein; B56; beta Catenin; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Carcinogenesis; Catalytic Domain; catenins; Cell Extracts; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; dephosphorylation; Enzyme Inhibitors - pharmacology; Epistasis, Genetic; glycogen synthase kinase; Glycogen Synthase Kinase 3; Humans; Marine Toxins; Microcystins; okadaic acid; Okadaic Acid - pharmacology; Ovum; Peptides, Cyclic - pharmacology; phosphoprotein phosphatase 2A; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; PP2A; Precipitin Tests; Protein Phosphatase 2; Proteins - metabolism; Proteins - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Repressor Proteins; Signal Transduction; Trans-Activators; Wnt; Wnt Proteins; Xenopus; Xenopus laevis - embryology; Xenopus Proteins; Zebrafish Proteins
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/20.15.4122

Wnt signaling increases β‐catenin abundance and transcription of Wnt‐responsive genes. Our previous work suggested that the B56 regulatory subunit of protein phosphatase 2A (PP2A) inhibits Wnt signaling. Okadaic acid (a phosphatase inhibitor) increases, while B56 expression reduces, β‐catenin abundance; B56 also reduces transcription of Wnt‐responsive genes. Okadaic acid is a tumor promoter, and the structural A subunit of PP2A is mutated in multiple cancers. Taken together, the evidence suggests that PP2A is a tumor suppressor. However, other studies suggest that PP2A activates Wnt signaling. We now show that the B56, A and catalytic C subunits of PP2A each have ventralizing activity in Xenopus embryos. B56 was epistatically positioned downstream of GSK3β and axin but upstream of β‐catenin, and axin co‐immunoprecipitated B56, A and C subunits, suggesting that PP2A:B56 is in the β‐catenin degradation complex. PP2A appears to be essential for β‐catenin degradation, since β‐catenin degradation was reconstituted in phosphatase‐depleted Xenopus egg extracts by PP2A, but not PP1. These results support the hypothesis that PP2A:B56 directly inhibits Wnt signaling and plays a role in development and carcinogenesis.