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. B56epsilon, 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 B56epsilon 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 B56epsilon 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 B56epsilon has important biological functions. Furthermore, we show that the N-terminal sequence of B56epsilon, which is not present in the shorter isoform, contains a nuclear localization signal, whereas the C terminus of B56epsilon 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 B56epsilon is alternatively translated adds a new level of regulation to PP2A holoenzymes.
Jin
Zhigang
Z
Center for Cell and Development Biology, the Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Ohio State University, Columbus, Ohio 43205, USA.
Shi
Jianli
J
Saraf
Amit
A
Mei
Wenyan
W
Zhu
Guo-Zhang
GZ
Strack
Stefan
S
Yang
Jing
J
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics; D004331:Drosophila melanogaster; D020035:Holoenzymes / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008636:Mesencephalon / Q000196:embryology* / Q000201:enzymology; D051379:Mice; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D012249:Rhombencephalon / Q000196:embryology* / Q000201:enzymology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000096:biosynthesis* / Q000235:genetics; D014982:Xenopus laevis
D029721:Drosophila Proteins; D020035:Holoenzymes; D007527:Isoenzymes; D019913:Nuclear Localization Signals; D012315:RNA Caps; D051153:Wnt Proteins; D029867:Xenopus Proteins; C517189:PPP2CA protein, human; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C079898:tws protein, Drosophila