The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness

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.

Gab2 and Src co-operate in human mammary epithelial cells to promote growth factor independence and disruption of acinar morphogenesis

“…Consequently, amplified PI3-kinase/Akt signalling in the v-Src-expressing cells may both suppress Erk activation and promote the dispersed phenotype. This is consistent with the ability of activated Akt to promote EMT of squamous cell carcinoma cells (Grille et al, 2003) and of PTEN to inhibit v-Src-induced adherens junction disassembly in Madin-Darby canine kidney (MDCK) cells (Kotelevets et al, 2001).…”

“…This is intriguing in light of reports that depending on context, PI3-kinase signalling can play positive or negative roles in the formation of E-cadherin-based adherens junctions. Thus, while PI3-kinase signalling enhances the formation of nascent adhesive contacts following E-cadherin homophilic ligation (Kovacs et al, 2002;Pang et al, 2005), in v-Src-expressing MDCK cells it promotes junctional instability, since cell-cell aggregation can be induced in an E-cadherin-dependent manner by expressing PTEN (Kotelevets et al, 2001). These contrasting effects are probably explained by marked differences in signal strength and duration.…”

“…This suggests that increased Src activity may contribute to the metastatic spread of epithelial cancers. Interestingly, expression of phosphatase and tensin homologue deleted from chromosome ten (PTEN), in v-Src-expressing epithelial cells stabilizes E-cadherin junctions and attenuates cell scattering and invasiveness, indicating that enhanced PI3-kinase signalling may underlie these biological effects of v-Src (Kotelevets et al, 2001).…”

Role of tissue stroma in cancer cell invasion

“…The lipid phosphatase activity of PTEN (phosphatase and tensin homologue deleted from chromosome 10) acts on lipid products of PI3K. Therefore PTEN might function as a potent gatekeeper to counteract N-cadherin-mediated invasion [204]. N-Cadherin-expressing retinal pigment epithelial cells are invasive in collagen type I.…”

PTEN: A Novel Anti-oncogenic Function Independent of Phosphatase Activity

“…16 In contrast, PTEN can increase E and N-cadherin expression in glioblastoma cell lines and, as a result, inhibit cell migration. 18 These results indicate that the subcellular localization of PTEN is critical in the regulation of its stability and its control of cell migration. This localization is controlled by phosphorylation of Ser/Thr residues, where unphosphorylated PTEN is predominantly localized at the cell membrane, while phosphorylated PTEN is found in the cytosolic fraction.…”