14-3-3 proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation

Academic Article

Abstract

  • © 2020 by The American Society for Biochemistry and Molecular Biology, Inc. Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain. As such, the function of the N terminus of this large protein remains poorly characterized. Here, using yeast two-hybrid screening, co-immunoprecipitation, and several biochemical assays, we found that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3 proteins bound TET2 when it was phosphorylated at Ser-99. In particular, we observed that AMP-activated protein kinase- mediated phosphorylation at Ser-99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine levels. The interaction of 14-3-3 proteins with TET2 protected the Ser-99 phosphorylation, and disruption of this interaction both reduced TET2 phosphorylation and decreased TET2 stability. Furthermore, we noted that protein phosphatase 2A can interact with TET2 and dephosphorylate Ser-99. Collectively, these results provide detailed insights into the role of the TET2 N-terminal domain in TET2 regulation. Moreover, they reveal the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels or activity.
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    Digital Object Identifier (doi)

    Author List

  • Kundu A; Shelar S; Ghosh AP; Ballestas M; Kirkman R; Nam H; Brinkley GJ; Karki S; Mobley JA; Bae S
  • Start Page

  • 1754
  • End Page

  • 1766
  • Volume

  • 295
  • Issue

  • 6