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The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network

Nature volume 455, pages 813–817 (2008)Cite this article

Abstract

Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression1,2,3,4,5,6. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear–cytoplasmic partitioning7. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML–RARα fusion oncoprotein. Remarkably, treatment with drugs that trigger PML–RARα degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML–DAXX–HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.

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Figure 1: Aberrant localization of PTEN in APL and Pml -null MEFs.
Figure 2: HAUSP interacts with and deubiquitinylates PTEN.
Figure 3: HAUSP regulates PTEN localization.
Figure 4: PML opposes HAUSP-mediated PTEN deubiquitinylation.

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Acknowledgements

We thank B. Vogelstein, K. H. Baek, M. Lanotte and X. Jiang for sharing reagents and W. Gu for critical discussions. We thank all members of the Pandolfi laboratory, in particular K. Ito, S. Majid and L. Poliseno, for technical support, advice and discussion. This work was supported by NIH grants to P.P.P. L.S. is supported by the International Human Frontier Science Program Organization, and A.C. is supported by the European Molecular Biology Organization.

Author Contributions The experiments were conceived and designed by M.S.S., L.S., A.C. and P.P.P. Experiments were performed by M.S.S., L.S., A.C. and A.E. F.L.-C. provided APL and AML samples. J.T.-F. provided and scored IHC of prostate cancer tissue microarray and APL samples. Data were analysed by M.S.S., L.S., A.C., J.T.-F. and P.P.P. The paper was written by M.S.S., L.S., A.C. and P.P.P.

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Author notes

  1. Leonardo Salmena and Arkaitz Carracedo: These authors contributed equally to this work.

Authors and Affiliations

  1. Beth Israel Deaconess Cancer Center and Department of Medicine, Cancer Genetics Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA,

    Min Sup Song, Leonardo Salmena, Arkaitz Carracedo, Ainara Egia & Pier Paolo Pandolfi

  2. Department of Biopathology, University of Tor Vergata, Rome 00133, Italy

    Francesco Lo-Coco

  3. Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA,

    Julie Teruya-Feldstein

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  1. Min Sup Song
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Correspondence to Pier Paolo Pandolfi.

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Song, M., Salmena, L., Carracedo, A. et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network. Nature 455, 813–817 (2008). https://doi.org/10.1038/nature07290

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