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The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness
L Kotelevets1, J van Hengel, E Bruyneel
1Institut National de la Santé et de la Recherche Médicale (INSERM) U410, Faculté de Médecine Bichat, 75018 Paris, France.
Abstract:
To analyze the implication of PTEN in the control of tumor cell invasiveness, the canine kidney epithelial cell lines MDCKras-f and MDCKts-src, expressing activated Ras and a temperature-sensitive v-Src tyrosine kinase, respectively, were transfected with PTEN expression vectors. Likewise, the human PTEN-defective glioblastoma cell lines U87MG and U373MG, the melanoma cell line FM-45, and the prostate carcinoma cell line PC-3 were transfected. We demonstrate that ectopic expression of wild-type PTEN in MDCKts-src cells, but not expression of PTEN mutants deficient in either the lipid or both the lipid and protein phosphatase activities, reverted the morphological transformation, induced cell-cell aggregation, and suppressed the invasive phenotype in an E-cadherin-dependent manner. In contrast, overexpression of wild-type PTEN did not counteract Ras-induced invasiveness of MDCKras-f cells expressing low levels of E-cadherin. PTEN effects were not associated with marked changes in accumulation or phosphorylation levels of E-cadherin and associated catenins. Wild-type, but not mutant, PTEN also reverted the invasive phenotype of U87MG, U373MG, PC-3, and FM-45 cells. Interestingly, PTEN effects were mimicked by N-cadherin-neutralizing antibody in the glioblastoma cell lines. Our data confirm the differential activities of E- and N-cadherin on invasiveness and suggest that the lipid phosphatase activity of PTEN exerts a critical role in stabilizing junctional complexes and restraining invasiveness.
Insights
The tumor suppressor PTEN, through its lipid phosphatase activity, restrains cancer cell invasion by stabilizing cell-cell adhesion complexes. This finding highlights PTEN
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Tumor cell invasiveness is a critical hallmark of cancer progression.
- PTEN (Phosphatase and tensin homolog) is a key tumor suppressor gene.
- The role of PTEN in regulating cell adhesion and invasion requires further elucidation.
Purpose of the Study:
- To investigate the role of PTEN in controlling tumor cell invasiveness.
- To determine the specific phosphatase activity of PTEN critical for its anti-invasive function.
- To explore the relationship between PTEN, E-cadherin, and N-cadherin in regulating cell invasion.
Main Methods:
- Transfection of cancer cell lines (MDCK, U87MG, U373MG, FM-45, PC-3) with wild-type and mutant PTEN expression vectors.
- Assessment of morphological transformation, cell-cell aggregation, and invasive phenotype.
- Analysis of E-cadherin and N-cadherin expression and function.
Main Results:
- Ectopic expression of wild-type PTEN suppressed invasiveness and induced cell-cell aggregation in MDCKts-src cells in an E-cadherin-dependent manner.
- PTEN's lipid phosphatase activity was essential for its anti-invasive effects.
- PTEN overexpression counteracted invasiveness in human cancer cell lines (U87MG, U373MG, PC-3, FM-45), an effect mimicked by N-cadherin neutralization.
- PTEN's effects were independent of significant changes in E-cadherin or catenin levels.
Conclusions:
- PTEN's lipid phosphatase activity is critical for stabilizing cell-cell adhesion complexes and restraining tumor cell invasiveness.
- E-cadherin and N-cadherin play differential roles in regulating cell invasiveness.
- PTEN acts as a crucial regulator of cell adhesion and invasion, offering potential therapeutic targets.