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

被引:97
作者
Tibarewal, Priyanka [1 ]
Zilidis, Georgios [1 ,2 ]
Spinelli, Laura [1 ]
Schurch, Nick [3 ]
Maccario, Helene [1 ]
Gray, Alexander [1 ]
Perera, Nevin M. [1 ]
Davidson, Lindsay [1 ]
Barton, Geoffrey J. [3 ]
Leslie, Nick R. [1 ]
机构
[1] Univ Dundee, Coll Life Sci, Div Cell Signalling & Immunol, Dundee DD1 5EH, Scotland
[2] Univ Dundee, Ninewells Hosp & Med Sch, Dept Neurosurg, Dundee DD1 9SY, Scotland
[3] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH, Scotland
基金
英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
MEMBRANE ASSOCIATION; SIGNALING PATHWAYS; EPITHELIAL-CELLS; PHOSPHORYLATION; POLARITY; 3-KINASE; KINASE; DOMAIN; MORPHOGENESIS; TUMORIGENESIS;
D O I
10.1126/scisignal.2002138
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
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页数:11
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