Proteomics

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14-3-3 protects AMPK phosphorylated TET2 from dephosphorylation by PP2A


ABSTRACT: Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Disease Free

SUBMITTER: james mobley  

LAB HEAD: James A. Mobley

PROVIDER: PXD016160 | Pride | 2020-01-13

REPOSITORIES: Pride

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Publications

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

Kundu Anirban A   Shelar Sandeep S   Ghosh Arindam P AP   Ballestas Mary M   Kirkman Richard R   Nam Hyeyoung H   Brinkley Garrett J GJ   Karki Suman S   Mobley James A JA   Bae Sejong S   Varambally Sooryanarayana S   Sudarshan Sunil S  

The Journal of biological chemistry 20200103 6


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-  ...[more]

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