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Sci. Signal., 28 February 2012
Vol. 5, Issue 213, p. ra18
[DOI: 10.1126/scisignal.2002138]


PTEN Protein Phosphatase Activity Correlates with Control of Gene Expression and Invasion, a Tumor-Suppressing Phenotype, But Not with AKT Activity

Priyanka Tibarewal1, Georgios Zilidis1,2*, Laura Spinelli1, Nick Schurch3, Helene Maccario1{dagger}, Alexander Gray1, Nevin M. Perera1, Lindsay Davidson1, Geoffrey J. Barton3, and Nick R. Leslie1{ddagger}

1 Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
2 Department of Neurosurgery, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
3 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

* Present address: University Hospital Southampton, NHS Foundation Trust, Southampton SO16 6YD, UK.

{dagger} Present Address: Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Abstract: The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has a well-characterized lipid phosphatase activity and a poorly characterized protein phosphatase activity. We show that both activities are required for PTEN to inhibit cellular invasion and to mediate most of its largest effects on gene expression. PTEN appears to dephosphorylate itself at threonine 366, and mutation of this site makes lipid phosphatase activity sufficient for PTEN to inhibit invasion. We propose that the dominant role for PTEN’s protein phosphatase activity is autodephosphorylation-mediated regulation of its lipid phosphatase activity. Because PTEN’s regulation of invasion and these changes in gene expression required lipid phosphatase activity, but did not correlate with the total cellular abundance of its phosphatidylinositol 3,4,5-trisphosphate (PIP3) lipid substrate or AKT activity, we propose that localized PIP3 signaling may play a role in those PTEN-mediated processes that depend on both its protein and lipid phosphatase activities. Finally, we identified a tumor-derived PTEN mutant selectively lacking protein phosphatase activity, indicating that in some circumstances the regulation of invasion and not that of AKT can correlate with PTEN-mediated tumor suppression.

{ddagger} To whom correspondence should be addressed. E-mail: n.r.leslie{at}

Citation: P. Tibarewal, G. Zilidis, L. Spinelli, N. Schurch, H. Maccario, A. Gray, N. M. Perera, L. Davidson, G. J. Barton, N. R. Leslie, PTEN Protein Phosphatase Activity Correlates with Control of Gene Expression and Invasion, a Tumor-Suppressing Phenotype, But Not with AKT Activity. Sci. Signal. 5, ra18 (2012).

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Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240.
T. R. Fenton, D. Nathanson, C. Ponte de Albuquerque, D. Kuga, A. Iwanami, J. Dang, H. Yang, K. Tanaka, S. M. Oba-Shinjo, M. Uno, et al. (2012)
PNAS 109, 14164-14169
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