The 48-kDa alternative translation isoform of PP2A:B56ε is required for Wnt signaling during midbrain-hindbrain boundary formation

Abstract

Alternative translation is an underappreciated post-transcriptional regulation mechanism. Although only a small number of genes are found to be alternatively translated, most genes undergoing alternative translation play important roles in tumorigenesis and development. Protein phosphatase 2A (PP2A) is involved in many cellular events during tumorigenesis and development. The specificity, localization, and activity of PP2A are regulated by B regulatory subunits. B56ε, a member of the B56 regulatory subunit family, is involved in multiple signaling pathways and regulates a number of developmental processes. Here we report that B56ε is alternatively translated, leading to the production of a full-length form and a shorter isoform that lacks the N-terminal 76 amino acid residues of the full-length form. Alternative translation of B56ε occurs through a cap-dependent mechanism. We provide evidence that the shorter isoform is required for Wnt signaling and regulates the midbrain/hindbrain boundary formation during Xenopus embryonic development. This demonstrates that the shorter isoform of B56ε has important biological functions. Furthermore, we show that the N-terminal sequence of B56ε, which is not present in the shorter isoform, contains a nuclear localization signal, whereas the C terminus of B56ε contains a nuclear export signal. The shorter isoform, which lacks the N-terminal nuclear localization signal, is restricted to the cytoplasm. In contrast, the full-length form can be localized to the nucleus in a cell type-specific manner. The finding that B56ε is alternatively translated adds a new level of regulation to PP2A holoenzymes. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.