TET2 stabilization by 14-3-3 binding to the phosphorylated Serine 99 is deregulated by mutations in cancer

Chen, Hao; Yu, Dingdang; Fang, Rui; Rabidou, Kimberlie; Wu, Di; Hu, Di; Jia, Peilin; Zhao, Zhongming; Wu, Zhiping; Peng, Junmin; Shi, Yang; Shi, Yujiang Geno

doi:10.1038/s41422-018-0132-5

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…We are aware of a recent communication that reported on 14-3-3 binding to TET2 (7). In this study, exogenous treatment Figure 6.…”

Section: Discussionmentioning

confidence: 69%

“…fusicoccin) of the interaction between 14-3-3 and client proteins have been reported (25,26). Such stabilizers may have particular relevance to TET2 mutant AML as a cluster of mutations around the Ser-99 site has been recently reported, which have diminished 14-3-3 binding and reduced protein stability (7). This group of TET2 mutant tumors may be more amenable to approaches that foster interaction with 14-3-3s.…”

Section: Dynamic Regulation Of Tet2 By 14-3-3mentioning

confidence: 99%

“…We demonstrate that several members of the 14-3-3 group of proteins bind to TET2 in a phosphorylation-dependent manner. Chen et al (7) recently reported this interaction and demonstrated that TET2 mutations that disrupt this association have reduced protein stability. In addition, they demonstrated that 14-3-3 inhibition led to decreased TET2 levels (7).…”

mentioning

confidence: 91%

“…Chen et al (7) recently reported this interaction and demonstrated that TET2 mutations that disrupt this association have reduced protein stability. In addition, they demonstrated that 14-3-3 inhibition led to decreased TET2 levels (7). They proposed that this interaction promotes TET2 stability by an undetermined mechanism.…”

mentioning

confidence: 91%

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

Kundu

Shelar

Ghosh

et al. 2020

Journal of Biological Chemistry

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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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“…We are aware of a recent communication that reported on 14-3-3 binding to TET2 (7). In this study, exogenous treatment Figure 6.…”

Section: Discussionmentioning

confidence: 69%

Section: Dynamic Regulation Of Tet2 By 14-3-3mentioning

confidence: 99%

mentioning

confidence: 91%

mentioning

confidence: 91%

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

Kundu

Shelar

Ghosh

et al. 2020

Journal of Biological Chemistry

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“…TET2, and possibly other TET proteins, is also regulated by p300-mediated acetylation, which promotes TET2 catalytic activity, protein stability, and binding with other partners and is counted by HDCA1/2-mediated deacetylation ( 38 ). TET2 was also found to be phosphorylated by AMP (adenosine 5′-monophosphate)–activated protein kinase (AMPK), which promotes TET2 binding to 14-3-3 and TET2 protein stability and is counted by protein phosphatase 2A (PP2A) ( 37 , 47 , 48 ). Our findings provide further evidence supporting the regulation of TET enzyme by reversible posttranslational modifications.…”

Section: Discussionmentioning

confidence: 99%

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

et al. 2020

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TET2 DNA dioxygenase is frequently mutated in human hematopoietic malignancies and functionally inactivated in many solid tumors through a nonmutational mechanism. We recently found that TET2 mediates the interferon-JAK-STAT pathway to stimulate chemokine expression and tumor infiltration of lymphocytes (TILs). TET2 is monoubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquitin and negatively regulates TET2 activity. Gene expression profiling demonstrates that TET2 and USP15 oppositely regulate genes involved in multiple inflammatory pathways, and TET2 is a major target of USP15 function. Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2-dependent manner, leading to increased response to immunotherapy and extended life span of tumor-bearing mice. These results reveal a previously unknown regulator of TET2 activity and suggest USP15 as a potential therapeutic target for immunotherapy of solid tumors.

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Mechanisms that regulate the activities of TET proteins

Joshi

Liu

et al. 2022

Cell. Mol. Life Sci.

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TET2 stabilization by 14-3-3 binding to the phosphorylated Serine 99 is deregulated by mutations in cancer

Cited by 7 publications

References 10 publications

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

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

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

Mechanisms that regulate the activities of TET proteins

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