Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Tachibana, M. et al. Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma. Cancer 94, 1955–1960 (2002)

    Article  CAS  Google Scholar 

  2. Whiteman, D. C. et al. Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma. Int. J. Cancer 99, 63–67 (2002)

    Article  CAS  Google Scholar 

  3. Zhou, X. P. et al. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am. J. Pathol. 157, 1123–1128 (2000)

    Article  CAS  Google Scholar 

  4. Zhou, X. P. et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am. J. Pathol. 161, 439–447 (2002)

    Article  CAS  Google Scholar 

  5. Perren, A. et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am. J. Pathol. 157, 1097–1103 (2000)

    Article  CAS  Google Scholar 

  6. Fridberg, M. et al. Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN. Leuk. Lymphoma 48, 2221–2232 (2007)

    Article  CAS  Google Scholar 

  7. Trotman, L. C. et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128, 141–156 (2007)

    Article  CAS  Google Scholar 

  8. Baker, S. J. PTEN enters the nuclear age. Cell 128, 25–28 (2007)

    Article  CAS  Google Scholar 

  9. Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007)

    Article  CAS  Google Scholar 

  10. Carracedo, A., Salmena, L. & Pandolfi, P. P. SnapShot: PTEN signaling pathways. Cell 133, 550– (2008)

    Article  CAS  Google Scholar 

  11. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008)

    Article  CAS  Google Scholar 

  12. Tallman, M. S. Acute promyelocytic leukemia as a paradigm for targeted therapy. Semin. Hematol. 41, 27–32 (2004)

    Article  CAS  Google Scholar 

  13. Lallemand-Breitenbach, V. et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor α degradation. J. Exp. Med. 193, 1361–1371 (2001)

    Article  CAS  Google Scholar 

  14. Lallemand-Breitenbach, V. et al. Arsenic degrades PML or PML-RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature Cell Biol. 10, 547–555 (2008)

    Article  CAS  Google Scholar 

  15. Tatham, M. H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature Cell Biol. 10, 538–546 (2008)

    Article  CAS  Google Scholar 

  16. Bernardi, R. & Pandolfi, P. P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nature Rev. Mol. Cell Biol. 8, 1006–1016 (2007)

    Article  CAS  Google Scholar 

  17. Salmena, L. & Pandolfi, P. P. Changing venues for tumour suppression: balancing destruction and localization by monoubiquitylation. Nature Rev. Cancer 7, 409–413 (2007)

    Article  CAS  Google Scholar 

  18. Everett, R. D. et al. A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J. 16, 1519–1530 (1997)

    Article  CAS  Google Scholar 

  19. Li, M. et al. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302, 1972–1975 (2003)

    Article  ADS  CAS  Google Scholar 

  20. van der Horst, A. et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biol. 8, 1064–1073 (2006)

    Article  CAS  Google Scholar 

  21. Marchenko, N. D., Wolff, S., Erster, S., Becker, K. & Moll, U. M. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J. 26, 923–934 (2007)

    Article  CAS  Google Scholar 

  22. Cummins, J. M. et al. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 428 doi: 10.1038/nature02501 (2004)

  23. Shen, T. H., Lin, H. K., Scaglioni, P. P., Yung, T. M. & Pandolfi, P. P. The mechanisms of PML-nuclear body formation. Mol. Cell 24, 331–339 (2006)

    Article  CAS  Google Scholar 

  24. Song, M. S., Song, S. J., Kim, S. Y., Oh, H. J. & Lim, D. S. The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2–DAXX–HAUSP complex. EMBO J. 27, 1863–1874 (2008)

    Article  CAS  Google Scholar 

  25. Tang, J. et al. Critical role for Daxx in regulating Mdm2. Nature Cell Biol. 8, 855–862 (2006)

    Article  CAS  Google Scholar 

  26. Lin, D. Y. et al. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol. Cell 24, 341–354 (2006)

    Article  CAS  Google Scholar 

  27. Liu, J. L. et al. Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation. Mol. Cell. Biol. 25, 6211–6224 (2005)

    Article  CAS  Google Scholar 

  28. Wang, X. et al. NEDD4–1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128, 129–139 (2007)

    Article  CAS  Google Scholar 

  29. Bernardi, R. et al. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nature Cell Biol. 6, 665–672 (2004)

    Article  CAS  Google Scholar 

  30. Scaglioni, P. P. et al. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126, 269–283 (2006)

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Pier Paolo Pandolfi.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-15 with Legends. (PDF 15671 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing