Wnt signaling increases beta -catenin abundance and transcription of Wnt-re
sponsive genes. Our previous work suggested that the B56 regulatory subunit
of protein phosphatase 2A (PP2A) inhibits Wnt signaling. Okadaic acid (a p
hosphatase inhibitor) increases, while B56 expression reduces, beta -cateni
n abundance; B56 also reduces transcription of Wnt-responsive genes. Okadai
c 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 si
gnaling. We now show that the B56, A and catalytic C subunits of PP2A each
have ventralizing activity in Xenopus embryos. B56 was epistatically positi
oned downstream of GSK3 beta and axin but upstream of beta -catenin, and ax
in 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 reconstitut
ed in phosphatase-depleted Xenopus egg extracts by PP2A, but not PP1. These
results support the hypothesis that PP2A:B56 directly inhibits Wnt signali
ng and plays a role in development and carcinogenesis.