Original Article

Oncogene (2010) 29, 687–697; doi:10.1038/onc.2009.384; published online 16 November 2009

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

L Davidson1,4, H Maccario1,4, N M Perera1,4, X Yang2,3, L Spinelli1, P Tibarewal1, B Glancy1, A Gray1, C J Weijer2, C P Downes1 and N R Leslie1

  1. 1Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, UK
  2. 2Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, UK

Correspondence: Dr NR Leslie, Division of Molecular Physiology, University of Dundee, Dow Street, Dundee, Scotland DD1 5EH, UK. E-mail: n.r.leslie@dundee.ac.uk

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

4These authors contributed equally to this work.

Received 1 April 2009; Revised 29 September 2009; Accepted 6 October 2009; Published online 16 November 2009.



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.


PTEN, PI3 kinase, phosphoinositide, cancer, TPIP, Akt