Skip to main content

Thank you for visiting nature.com. 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:

WWP2 is an E3 ubiquitin ligase for PTEN

Nature Cell Biology volume 13, pages 728–733 (2011)Cite this article

Subjects

Abstract

PTEN, a lipid phosphatase, is one of the most frequently mutated tumour suppressors in human cancer. Several recent studies have highlighted the importance of ubiquitylation in regulating PTEN tumour-suppressor function, but the enzymatic machinery required for PTEN ubiquitylation is not clear. In this study, by using a tandem affinity-purification approach, we have identified WWP2 (also known as atrophin-1-interacting protein 2, AIP-2) as a PTEN-interacting protein. WWP2 is an E3 ubiquitin ligase that belongs to the NEDD4-like protein family, which is involved in regulating transcription, embryonic stem-cell fate, cellular transport and T-cell activation processes. We show that WWP2 physically interacts with PTEN and mediates its degradation through a ubiquitylation-dependent pathway. Functionally, we show that WWP2 controls cellular apoptosis and is required for tumorigenicity of cells. Collectively, our results reveal a functional E3 ubiquitin ligase for PTEN that plays a vital role in tumour-cell survival.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: WWP2 interacts with PTEN.
Figure 2: WWP2 regulates PTEN protein stability by polyubiquitylation.
Figure 3: WWP2 activates AKT signalling and regulates stress-induced cell death in a PTEN-dependent manner.
Figure 4: WWP2 is required for tumorigenicity of cells.

Similar content being viewed by others

References

  1. Carnero, A., Blanco-Aparicio, C., Renner, O., Link, W. & Leal, J. F. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Current Cancer Drug Targets 8, 187–198 (2008).

    CAS  PubMed  Google Scholar 

  2. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

    Article  CAS  Google Scholar 

  3. Steck, P.A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15, 356–362 (1997).

    Article  CAS  Google Scholar 

  4. Guldberg, P. et al. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 57, 3660–3663 (1997).

    CAS  PubMed  Google Scholar 

  5. Rhei, E. et al. Mutation analysis of the putative tumour suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 57, 3657–3659 (1997).

    CAS  PubMed  Google Scholar 

  6. Wang, S. I., Parsons, R. & Ittmann, M. Homozygous deletion of the PTEN tumour suppressor gene in a subset of prostate adenocarcinomas. Clin. Cancer Res. 4, 811–815 (1998).

    CAS  PubMed  Google Scholar 

  7. Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183–4186 (1997).

    CAS  PubMed  Google Scholar 

  8. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

    Article  CAS  Google Scholar 

  9. Kwabi-Addo, B. et al. Haploinsufficiency of the Pten tumour suppressor gene promotes prostate cancer progression. Proc. Natl. Acad. Sci. USA 98, 11563–11568 (2001).

    Article  CAS  Google Scholar 

  10. Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).

    Article  Google Scholar 

  11. Blumenthal, G. M. & Dennis, P. A. PTEN hamartoma tumour syndromes. Euro. J. Hum. Genet. 16, 1289–1300 (2008).

    Article  CAS  Google Scholar 

  12. Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67 (1997).

    Article  CAS  Google Scholar 

  13. Marsh, D. J. et al. Germline mutations in PTEN are present in Bannayan–Zonana syndrome. Nat. Genet. 16, 333–334 (1997).

    Article  CAS  Google Scholar 

  14. Myers, M.P. et al. The lipid phosphatase activity of PTEN is critical for its tumour supressor function. Proc. Natl. Acad. Sci. USA 95, 13513–13518 (1998).

    Article  CAS  Google Scholar 

  15. Myers, M. P. et al. P-TEN, the tumour suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc. Natl. Acad. Sci. USA 94, 9052–9057 (1997).

    Article  CAS  Google Scholar 

  16. Osaki, M., Oshimura, M. & Ito, H. PI3K–AKT pathway: its functions and alterations in human cancer. Apoptosis 9, 667–676 (2004).

    Article  CAS  Google Scholar 

  17. Paez, J. & Sellers, W. R. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signalling. Cancer Treatment Res. 115, 145–167 (2003).

    Article  CAS  Google Scholar 

  18. Maddika, S. et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist. Updat. 10, 13–29 (2007).

    Article  CAS  Google Scholar 

  19. Stambolic, V. et al. Negative regulation of PKB/AKT-dependent cell survival by the tumour suppressor PTEN. Cell 95, 29–39 (1998).

    Article  CAS  Google Scholar 

  20. Reddy, P. et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 319, 611–613 (2008).

    Article  CAS  Google Scholar 

  21. Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    Article  CAS  Google Scholar 

  22. Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).

    Article  CAS  Google Scholar 

  23. Wang, X. & Jiang, X. Post-translational regulation of PTEN. Oncogene 27, 5454–5463 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Fouladkou, F. et al. The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc. Natl. Acad. Sci. USA 105, 8585–8590 (2008).

    Article  CAS  Google Scholar 

  26. Chen, A. et al. The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination. Mol. Cellular Biol. 29, 5348–5356 (2009).

    Article  CAS  Google Scholar 

  27. Li, H. et al. WWP2-mediated ubiquitination of the RNA polymerase II large subunit in mouse embryonic pluripotent stem cells. Mol. Cellular Biol. 27, 5296–5305 (2007).

    Article  CAS  Google Scholar 

  28. McDonald, F. J. et al. Ubiquitin–protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel. Am. J. Physiol. Renal Physiol. 283, F431–F436 (2002).

    Article  CAS  Google Scholar 

  29. Xu, H. M. et al. WWP2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination. J. Biol. Chem. 279, 23495–23503 (2004).

    Article  CAS  Google Scholar 

  30. Yim, E. K. et al. Rak functions as a tumour suppressor by regulating PTEN protein stability and function. Cancer Cell 15, 304–314 (2009).

    Article  CAS  Google Scholar 

  31. Georgescu, M. M. et al. Stabilization and productive positioning roles of the C2 domain of PTEN tumour suppressor. Cancer Res. 60, 7033–7038 (2000).

    CAS  PubMed  Google Scholar 

  32. Andres-Pons, A. et al. In vivo functional analysis of the counterbalance of hyperactive phosphatidylinositol 3-kinase p110 catalytic oncoproteins by the tumour suppressor PTEN. Cancer Res. 67, 9731–9739 (2007).

    Article  CAS  Google Scholar 

  33. He, X., Ni, Y., Wang, Y., Romigh, T. & Eng, C. Naturally occurring germline and tumour-associated mutations within the ATP-binding motifs of PTEN lead to oxidative damage of DNA associated with decreased nuclear p53. Human Mol. Genet. 20, 80–89 (2011).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  35. Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K. & Donner, D. B. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J. Biol. Chem. 277, 5484–5489 (2002).

    Article  CAS  Google Scholar 

  36. Zhou, M., Gu, L., Findley, H. W., Jiang, R. & Woods, W. G. PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer Res. 63, 6357–6362 (2003).

    CAS  PubMed  Google Scholar 

  37. Kato, H. et al. Functional evaluation of p53 and PTEN gene mutations in gliomas. Clin. Cancer Res. 6, 3937–3943 (2000).

    CAS  PubMed  Google Scholar 

  38. Jin, G. et al. PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer 69, 279–283 (2010).

    Article  Google Scholar 

  39. Bernassola, F., Karin, M., Ciechanover, A. & Melino, G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 14, 10–21 (2008).

    Article  CAS  Google Scholar 

  40. Maddika, S. & Chen, J. Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat. Cell Biol. 11, 409–419 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant from the Department of Biotechnology, Ministry of Science and Technology, India (to S.M.; BT/PR13134/GBD/27/202/2009), an Era of Hope Research Scholar Award (to J.C.; W81XWH-09-0409) and an NIH SPORE award (to J.N.S.; CA108961). J.C. is the recipient of an Era of Hope Scholar award from the Department of Defense (W81XWH-05-0470) and a member of MD Anderson Cancer Center (CA016672). S.K., N.R. and V.R.P. acknowledge fellowship support from the Department of Biotechnology, Council of Scientific and Industrial Research and University Grants Commission, India, respectively. S.M. is a recipient of the Department of Biotechnology’s IYBA award. We also acknowledge the Institute of Life Sciences, Hyderabad, for providing basic support during some parts of this work.

Author information

Authors and Affiliations

  1. Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India

    Subbareddy Maddika, Sridhar Kavela, Neelam Rani & Vivek Reddy Palicharla

  2. Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA

    Jenny L. Pokorny & Jann N. Sarkaria

  3. Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

    Junjie Chen

Authors
  1. Subbareddy Maddika
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sridhar Kavela
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neelam Rani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vivek Reddy Palicharla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jenny L. Pokorny
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jann N. Sarkaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Junjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.M., S.K., N.R. and V.R.P. carried out most of the experiments. J.L.P. and J.N.S. carried out the in vivo xenograft experiments. S.M. and J.C. designed the experiments, analysed the data and wrote the manuscript.

Corresponding authors

Correspondence to Subbareddy Maddika or Junjie Chen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 725 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maddika, S., Kavela, S., Rani, N. et al. WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol 13, 728–733 (2011). https://doi.org/10.1038/ncb2240

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2240

This article is cited by

Search

Advanced search

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