The 48 kDa alternative translation isoform of PP2A:B56epsilon is required for Wnt Signaling during Midbrain-Hindbrain Boundary Formation

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. B56e, a member of B56 regulatory subunit family, is involved in multiple signaling pathways and regulates a number of developmental processes. Here, we report that B56e 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 B56e occurs through a context-dependent leaky scanning mechanism. To investigate the functions of B56e alternative translation isoform, we depleted the shorter isoform and found that it is required for Wnt signaling and regulates the midbrain/hindbrain boundary formation during Xenopus embryonic development. This demonstrates that the shorter isoform of B56e has important biological functions. In addition, we provide evidence that the shorter isoform of B56e lacks a N-terminal nuclear localization signal. Unlike the full-length form, which can be localized to both the nucleus and cytoplasm, the shorter isoform of B56e is restricted to the cytoplasm. The finding that B56e is alternatively translated adds new level of regulation to PP2A holoenzymes.