The Wnt pathway is a key regulator of development and tumorigenesis. Its activation leads to increased ?-catenin abundance and ?-catenin-dependent transcription. Reversible protein phosphorylation is a fundamental mechanism for regulating protein function, and while the role of numerous kinases in Wnt signaling is well documented, the role of protein phosphatases is not as well defined. We identified an inhibitory role for the B56a regulatory subunit of protein phosphatase 2A (PP2A) in Wnt signaling. PP2A is a serine/threonine phosphatase heterotrimer comprised of a structural A, catalytic C, and regulatory B subunit. The B56 subfamily has several isoforms. B56a reduces ?-catenin abundance and ?-catenin-dependent gene expression, and blocks formation of primary body axes and Wnt-induced secondary axes in Xenopus laevis. One group has found that B56? reduces ?-catenin abundance in mice when overexpressed in the lung, while others have shown that B56e is required for Wnt signaling. Colon cancer, which is the second leading cause of cancer deaths in the United States, appears to depend on Wnt pathway deregulation. Interestingly, two PP2A A subunit mutations identified in human cancers do not bind B56, but bind PP2A C and other B regulatory subunits at near wild-type levels, suggesting that these PP2A A subunit mutations cause a loss of B56-specific, rather than global, PP2A activity. Since these are cancer-associated mutations, this also suggests that the loss of B56-specific PP2A activity is involved in tumorigenesis. Xenopus laevis is an excellent model system with which to studysignal transduction pathways. Signal transduction pathways are important in development, and their deregulation is frequently associated with cancer. We will use Xenopus laevis as a model system to investigate the mechanism by which B56 affects Wnt signaling. We will (1) analyze spatiotemporal expression patterns using real-time reverse transcriptase polymerase chain reaction and insitu hybridization, (2) examine B56a and B56? loss-of-function phenotypes in early Xenopus development using antisense morpholino oligonucleotides, and (3) determine whether known cancer-associated PP2A A mutations, as well as dominant-negative PP2A C mutations, activate Wnt signaling by examining their ability modulate ?-catenin half-life in Xenopus egg extracts and to induce secondary body axes in Xenopus embryos. The proposed work will help us better understand the regulation of the Wnt pathway, and therefore better understand colon tumorigenesis. A detailed understanding of colon tumorigenesis may lead to innovative approaches for the treatment and prevention of cancer.
Colon cancer, which is the second leading cause of cancer deaths in the United States, appears to depend on the overactivity of the Wnt cell-cell signaling pathway. We found that the B56a regulatory subunit of protein phosphatase 2A inhibits theWnt pathway. A clearer understanding of how B56a inhibits Wnt signaling will allow us to better understand colon tumorigenesis and may lead to innovative approaches for the treatment and prevention of one of the most deadly cancers. ? ? ? ?
| Teran, Evelyn; Branscomb, Aron D; Seeling, Joni M (2009) Dpr Acts as a molecular switch, inhibiting Wnt signaling when unphosphorylated, but promoting Wnt signaling when phosphorylated by casein kinase Idelta/epsilon. PLoS One 4:e5522 |
