Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus.
Wnt signaling increases beta-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, beta-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 GSK3beta and axin but upstream of beta-catenin, and axin co-immunoprecipitated B56, A and C subunits, suggesting that PP2A:B56 is in the beta-catenin degradation complex. PP2A appears to be essential for beta-catenin degradation, since beta-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.
Li
X
X
Department of Oncological Sciences and the Center for Children, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Yost
H J
HJ
Virshup
D M
DM
Seeling
J M
JM
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D020134:Catalytic Domain; D002457:Cell Extracts; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004843:Epistasis, Genetic; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins; D019319:Okadaic Acid / Q000494:pharmacology; D010063:Ovum; D010456:Peptides, Cyclic / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D054648:Protein Phosphatase 2; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins; D015398:Signal Transduction; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097847:Protein Phosphatase Inhibitory Proteins
D000957:Antigens, Viral, Tumor; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002457:Cell Extracts; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D008387:Marine Toxins; D052998:Microcystins; D019319:Okadaic Acid; D010456:Peptides, Cyclic; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; C555454:axin1 protein, Xenopus; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C057862:cyanoginosin LR