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.

  • Original Article
  • Published:

Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN

Oncogene volume 29, pages 687–697 (2010)Cite this article

Abstract

PTEN is a tumour suppressor with phosphatase activity in vitro against both lipids and proteins and other potential non-enzymatic mechanisms of action. Although the importance of PTEN's lipid phosphatase activity in regulating the PI3K signalling pathway is recognized, the significance of PTEN's other mechanisms of action is currently unclear. In this study, we describe the systematic identification of a PTEN mutant, PTEN Y138L, with activity against lipid, but not soluble substrates. Using this mutant, we provide evidence for the interfacial activation of PTEN against lipid substrates. We also show that when re-expressed at physiological levels in PTEN null U87MG glioblastoma cells, the protein phosphatase activity of PTEN is not required to regulate cellular PtdInsP3 levels or the downstream protein kinase Akt/PKB. Finally, in three-dimensional Matrigel cultures of U87MG cells similarly re-expressing PTEN mutants, both the protein and lipid phosphatase activities were required to inhibit invasion, but either activity alone significantly inhibited proliferation, albeit only weakly for the protein phosphatase activity. Our data provide a novel tool to address the significance of PTEN's separable lipid and protein phosphatase activities and suggest that both activities suppress proliferation and together suppress invasion.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Campbell RB, Liu F, Ross AH . (2003). Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate. J Biol Chem 278: 33617–33620.

    Article  CAS  PubMed  Google Scholar 

  • Cheney IW, Johnson DE, Vaillancourt MT, Avanzini J, Morimoto A, Demers GW et al. (1998). Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res 58: 2331–2334.

    CAS  PubMed  Google Scholar 

  • Chow LM, Baker SJ . (2006). PTEN function in normal and neoplastic growth. Cancer Lett 241: 184–196.

    Article  CAS  PubMed  Google Scholar 

  • Das S, Dixon JE, Cho W . (2003). Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci USA 100: 7491–7496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davies MA, Lu Y, Sano T, Fang X, Tang P, LaPushin R et al. (1998). Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res 58: 5285–5290.

    CAS  PubMed  Google Scholar 

  • de Bouard S, Christov C, Guillamo JS, Kassar-Duchossoy L, Palfi S, Leguerinel C et al. (2002). Invasion of human glioma biopsy specimens in cultures of rodent brain slices: a quantitative analysis. J Neurosurg 97: 169–176.

    Article  PubMed  Google Scholar 

  • Deleu S, Choi K, Pesesse X, Cho J, Sulis ML, Parsons R et al. (2006). Physiological levels of PTEN control the size of the cellular Ins(1,3,4,5,6)P(5) pool. Cell Signal 18: 488–498.

    Article  CAS  PubMed  Google Scholar 

  • Dey N, Crosswell HE, De P, Parsons R, Peng Q, Su JD et al. (2008). The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. Cancer Res 68: 1862–1871.

    Article  CAS  PubMed  Google Scholar 

  • Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R et al. (2003). PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3: 117–130.

    Article  CAS  PubMed  Google Scholar 

  • Furnari FB, Huang HJ, Cavenee WK . (1998). The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res 58: 5002–5008.

    CAS  PubMed  Google Scholar 

  • Furnari FB, Lin H, Huang HS, Cavenee WK . (1997). Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 94: 12479–12484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gil A, Andres-Pons A, Pulido R . (2007). Nuclear PTEN: a tale of many tails. Cell Death Differ 14: 395–399.

    Article  CAS  PubMed  Google Scholar 

  • Gildea JJ, Herlevsen M, Harding MA, Gulding KM, Moskaluk CA, Frierson HF et al. (2004). PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatase activity. Oncogene 23: 6788–6797.

    Article  CAS  PubMed  Google Scholar 

  • Goldbrunner RH, Bernstein JJ, Tonn JC . (1998). ECM-mediated glioma cell invasion. Microsc Res Tech 43: 250–257.

    Article  CAS  PubMed  Google Scholar 

  • Gray A, Olsson H, Batty IH, Priganica L, Peter Downes C . (2003). Nonradioactive methods for the assay of phosphoinositide 3-kinases and phosphoinositide phosphatases and selective detection of signaling lipids in cell and tissue extracts. Anal Biochem 313: 234–245.

    Article  CAS  PubMed  Google Scholar 

  • Gu J, Tamura M, Pankov R, Danen EH, Takino T, Matsumoto K et al. (1999). Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol 146: 389–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hjelmeland AB, Hjelmeland MD, Shi Q, Hart JL, Bigner DD, Wang XF et al. (2005). Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity. Cancer Res 65: 11276–11281.

    Article  CAS  PubMed  Google Scholar 

  • Iijima M, Huang YE, Luo HR, Vazquez F, Devreotes PN . (2004). Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis. J Biol Chem 279: 16606–16613.

    Article  CAS  PubMed  Google Scholar 

  • Ikeda Y, Takeuchi Y, Martin F, Cosset FL, Mitrophanous K, Collins M . (2003). Continuous high-titer HIV-1 vector production. Nat Biotechnol 21: 569–572.

    Article  CAS  PubMed  Google Scholar 

  • Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L et al. (2006). Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. Nat Med 12: 324–329.

    Article  CAS  PubMed  Google Scholar 

  • Keniry M, Parsons R . (2008). The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27: 5477–5485.

    Article  CAS  PubMed  Google Scholar 

  • Lackey J, Barnett J, Davidson L, Batty IH, Leslie NR, Downes CP . (2007). Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling. Oncogene 26: 7132–7142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y et al. (1999). Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99: 323–334.

    Article  CAS  PubMed  Google Scholar 

  • Leslie NR, Batty IH, Maccario H, Davidson L, Downes CP . (2008). Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene 27: 5464–5476.

    Article  CAS  PubMed  Google Scholar 

  • Leslie NR, Yang X, Downes CP, Weijer CJ . (2007). PtdIns(3,4,5)P(3)-dependent and -independent roles for PTEN in the control of cell migration. Curr Biol 17: 115–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z et al. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16: 64–67.

    Article  CAS  PubMed  Google Scholar 

  • Maccario H, Perera NM, Davidson L, Downes CP, Leslie NR . (2007). PTEN is destabilized by phosphorylation on Thr366. Biochem J 405: 439–444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahimainathan L, Choudhury GG . (2004). Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novel mechanism of action of the phosphatase. J Biol Chem 279: 15258–15268.

    Article  CAS  PubMed  Google Scholar 

  • McConnachie G, Pass I, Walker SM, Downes CP . (2003). Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids. Biochem J 371: 947–955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA et al. (1998). The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA 95: 13513–13518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH et al. (1997). P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA 94: 9052–9057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ning K, Miller LC, Laidlaw HA, Burgess LA, Perera NM, Downes CP et al. (2006). A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic beta-cells. EMBO J 25: 2377–2387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okumura K, Zhao M, Depinho RA, Furnari FB, Cavenee WK . (2005). Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor. Proc Natl Acad Sci USA 102: 2703–2706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orchiston EA, Bennett D, Leslie NR, Clarke RG, Winward L, Downes CP et al. (2004). PTEN M-CBR3, a versatile and selective regulator of inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5). Evidence for Ins(1,3,4,5,6)P5 as a proliferative signal. J Biol Chem 279: 1116–1122.

    Article  CAS  PubMed  Google Scholar 

  • Park MJ, Kim MS, Park IC, Kang HS, Yoo H, Park SH et al. (2002). PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res 62: 6318–6322.

    CAS  PubMed  Google Scholar 

  • Raftopoulou M, Etienne-Manneville S, Self A, Nicholls S, Hall A . (2004). Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science 303: 1179–1181.

    Article  CAS  PubMed  Google Scholar 

  • Redfern RE, Redfern D, Furgason ML, Munson M, Ross AH, Gericke A . (2008). PTEN phosphatase selectively binds phosphoinositides and undergoes structural changes. Biochemistry 47: 2162–2171.

    Article  CAS  PubMed  Google Scholar 

  • Salmena L, Carracedo A, Pandolfi PP . (2008). Tenets of PTEN tumor suppression. Cell 133: 403–414.

    Article  CAS  PubMed  Google Scholar 

  • Sansal I, Sellers WR . (2004). The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22: 2954–2963.

    Article  CAS  PubMed  Google Scholar 

  • Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP et al. (2007). Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128: 157–170.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki A, Nakano T, Mak TW, Sasaki T . (2008). Portrait of PTEN: messages from mutant mice. Cancer Sci 99: 209–213.

    Article  CAS  PubMed  Google Scholar 

  • Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM . (1998). Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280: 1614–1617.

    Article  CAS  PubMed  Google Scholar 

  • Tapparel C, Reymond A, Girardet C, Guillou L, Lyle R, Lamon C et al. (2003). The TPTE gene family: cellular expression, subcellular localization and alternative splicing. Gene 323: 189–199.

    Article  CAS  PubMed  Google Scholar 

  • Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H et al. (2007). Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141–156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR . (2001). Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276: 48627–48630.

    Article  CAS  PubMed  Google Scholar 

  • Vogelmann R, Nguyen-Tat MD, Giehl K, Adler G, Wedlich D, Menke A . (2005). TGFbeta-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN. J Cell Sci 118: 4901–4912.

    Article  CAS  PubMed  Google Scholar 

  • Walker SM, Downes CP, Leslie NR . (2001). TPIP: a novel phosphoinositide 3-phosphatase. Biochem J 360: 277–283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker SM, Leslie NR, Perera NM, Batty IH, Downes CP . (2004). The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. Biochem J 379: 301–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Dormann D, Munsterberg AE, Weijer CJ . (2002). Cell movement patterns during gastrulation in the chick are controlled by positive and negative chemotaxis mediated by FGF4 and FGF8. Dev Cell 3: 425–437.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Sam Swift and Paul Appleton from the Dundee Light Microscopy Facility for their help with image acquisition and analysis. We thank Hilary McLauchlan, James Hastie and their staff in the DSTT (University of Dundee) for provision of purified antibodies and recombinant protein kinases and Steven Hubbard for advice regarding data analysis. NL is an RCUK Academic Fellow. Work in the Inositol Lipid Signalling laboratory was funded by the Medical Research Council, the Association for International Cancer Research and the pharmaceutical companies of the DSTT consortium (Astra Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck KGaA and Pfizer).

Author information

Author notes

  1. X Yang

    Present address: 3Current address: Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632, PR China.,

  2. L Davidson, H Maccario and N M Perera: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, UK

    L Davidson, H Maccario, N M Perera, L Spinelli, P Tibarewal, B Glancy, A Gray, C P Downes & N R Leslie

  2. Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, UK

    X Yang & C J Weijer

Authors
  1. L Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Maccario
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N M Perera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Spinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Tibarewal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Glancy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C J Weijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C P Downes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N R Leslie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N R Leslie.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davidson, L., Maccario, H., Perera, N. et al. Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. Oncogene 29, 687–697 (2010). https://doi.org/10.1038/onc.2009.384

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.384

Keywords

This article is cited by

Search

Advanced search

Quick links