The role of B56 regulatory subunits of protein phosphatase 2A in Wnt signaling in Xenopus laevis
Sam Houston State UniversityGeneral/Lab Phone: 023 9284 8484
The Wnt pathway is a key regulator of cell growth and development. Perturbation of Wnt signaling during embryogenesis causes developmental abnormalities, while its postembryonic deregulation causes cancer. In fact, colon cancer, which is the second leading cause of cancer deaths in the United States, appears to require Wnt pathway deregulation. Phosphorylation plays a key role in the regulation of Wnt signaling, and while the role of numerous kinases in Wnt signaling is well documented, the role of protein phosphatases is not as well defined. We found that B56 regulatory subunits of protein phosphatase 2A (PP2A) can inhibit Wnt signaling. PP2A is a serine/threonine phosphatase comprised of a structural A subunit, catalytic C subunit, and regulatory B subunit. There are at least three families of B subunits: PR55, B56, and PR72. There is the potential for as many as two hundred distinct PP2A holoenzymes, since the A and C subunits, as well as each B subunit family, are encoded by multiple genes. In humans, B56 is encoded by five genes (B56a, B56b, B56g, B56d, and B56e) that share a 71-88% identical 400 amino acid core region and variable N- and C-terminal domains. Inhibition of PP2A activity causes cell proliferation and aberrant development, e.g., the phosphatase inhibitor okadaic acid induces skin and gastrointestinal tract cancers, and small and middle t DNA tumor virus antigens enhance cell growth through PP2A inhibition. Individual B56 isoforms appear to have diverse roles in Wnt signaling, e.g., while we and others have shown that B56a and B56g inhibit Wnt signaling, whereas another group detailed a developmental requirement for Xenopus B56e in Wnt signaling. Our research goals are to understand the complex roles that B56 isoforms play in the regulation of Wnt signaling in both development and disease. We use Xenopus embryos, mammalian cells, and biochemical assays to further characterize the distinct roles of B56 isoforms in Wnt signaling through both gain- and loss-of-function experiments. In addition, we are examining whether cancer-associated mutant PP2A subunits influence Wnt signaling.