PTEN Protein Phosphatase Activity Is Not Required for Tumour Suppression in the Mouse Prostate
Helen M. Wise,
Adam Harris,
Nisha Kriplani,
Adam Schofield,
Helen Caldwell,
Mark J. Arends,
Ian M. Overton,
Nick R. Leslie
Affiliations
Helen M. Wise
Institute of Biological Chemistry, Biophysics and Bioengineering, Riccarton Campus, Heriot Watt University, Nasmyth Building, Edinburgh EH14 4AS, UK
Adam Harris
Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, 97 Lisburn Road, Belfast BT9 7AE, UK
Nisha Kriplani
Institute of Biological Chemistry, Biophysics and Bioengineering, Riccarton Campus, Heriot Watt University, Nasmyth Building, Edinburgh EH14 4AS, UK
Adam Schofield
Institute of Biological Chemistry, Biophysics and Bioengineering, Riccarton Campus, Heriot Watt University, Nasmyth Building, Edinburgh EH14 4AS, UK
Helen Caldwell
Edinburgh Pathology, Cancer Research UK Edinburgh Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK
Mark J. Arends
Edinburgh Pathology, Cancer Research UK Edinburgh Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK
Ian M. Overton
Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, 97 Lisburn Road, Belfast BT9 7AE, UK
Nick R. Leslie
Institute of Biological Chemistry, Biophysics and Bioengineering, Riccarton Campus, Heriot Watt University, Nasmyth Building, Edinburgh EH14 4AS, UK
Loss PTEN function is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase activity. Using a mutant enzyme, PTEN Y138L, which selectively lacks protein phosphatase activity, we characterised genetically modified mice lacking either the full function of PTEN in the prostate gland or only lacking protein phosphatase activity. The phenotypes of mice carrying a single allele of either wild-type Pten or PtenY138L in the prostate were similar, with common prostatic intraepithelial neoplasia (PIN) and similar gene expression profiles. However, the latter group, lacking PTEN protein phosphatase activity additionally showed lymphocyte infiltration around PIN and an increased immune cell gene expression signature. Prostate adenocarcinoma, elevated proliferation and AKT activation were only frequently observed when PTEN was fully deleted. We also identify a common gene expression signature of PTEN loss conserved in other studies (including Nkx3.1, Tnf and Cd44). We provide further insight into tumour development in the prostate driven by loss of PTEN function and show that PTEN protein phosphatase activity is not required for tumour suppression.
