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Deubiquitylation and stabilization of PTEN by USP13

Nature Cell Biology volume 15, pages 14861494 (2013) | Download Citation

Abstract

The tumour suppressor PTEN is frequently lost in human cancers. In addition to gene mutations and deletions, recent studies have revealed the importance of post-translational modifications, such as ubiquitylation, in the regulation of PTEN stability, activity and localization. However, the deubiquitylase that regulates PTEN polyubiquitylation and protein stability remains unknown. Here we screened a total of 30 deubiquitylating enzymes (DUBs) and identified five DUBs that physically associate with PTEN. One of them, USP13, stabilizes the PTEN protein through direct binding and deubiquitylation of PTEN. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage-independent growth, glycolysis and tumour growth through downregulation of PTEN. Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN-positive but not PTEN-null breast cancer cells. Importantly, USP13 protein is downregulated in human breast tumours and correlates with PTEN protein levels. These findings identify USP13 as a tumour-suppressing protein that functions through deubiquitylation and stabilization of PTEN.

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Acknowledgements

We thank J. Yuan, Z. Gong, A. Sorokin, J. Wang, N. Li, L. Feng and L. Li for reagents and technical assistance. This work is supported by US National Institutes of Health grants R00CA138572 (to L.M.) and R01CA166051 (to L.M.) and a Cancer Prevention and Research Institute of Texas Scholar Award R1004 (to L.M.).

Author information

Author notes

    • Peijing Zhang
    •  & Yongkun Wei

    These authors contributed equally to this work

Affiliations

  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jinsong Zhang
    • , Peijing Zhang
    • , Hai-long Piao
    • , Wenqi Wang
    • , Min Wang
    • , Dahu Chen
    • , Junjie Chen
    •  & Li Ma
  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Yongkun Wei
    • , Yutong Sun
    •  & Mien-Chie Hung
  3. Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India

    • Subbareddy Maddika
  4. Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA

    • Mien-Chie Hung
    • , Junjie Chen
    •  & Li Ma
  5. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan

    • Mien-Chie Hung

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Contributions

J.Z. and L.M. conceived and designed the study and wrote the manuscript. J.Z. performed most of the experiments. P.Z. contributed to DUB library construction and in vitro deubiquitylation assays. Y.W. and M-C.H. performed studies on tissue microarrays of human patient samples. H-l.P. performed xenograft implantation. W.W. and J.C. assisted with tandem affinity purification and mass spectrometric analysis. S.M. provided the PTEN mutant constructs. M.W. assisted with animal care. D.C. assisted with lactate secretion assays. Y.S. maintained shRNA and ORF clones and assisted with glucose uptake assays.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Li Ma.

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DOI

https://doi.org/10.1038/ncb2874

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