Implication of the MAGI-1b/PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness

ABSTRACT We recently established the critical role of the lipid phosphatase activity of the PTEN tumor suppressor in stabilizing cell‐cell contacts and suppressing invasiveness. To delineate the effector systems involved, we investigated the interaction of PTEN with E‐cadherin junctional complexes in kidney and colonic epithelial cell lines. PTEN and the p85 regulatory subunit of phosphatidylinositol 3‐OH kinase (PI3K) co‐immunoprecipitated with E‐cadherin and catenins. By using a yeast two‐hybrid assay, we demonstrated that PTEN interacted indirectly with β‐ catenin by binding the scaffolding protein MAGI‐1b. This model was corroborated in various ways in mammalian cells. Ectopic expression of MAGI‐1b potentiated the interaction of PTEN with junctional complexes, promoted E‐cadherin‐dependent cell‐cell aggregation, and reverted the Src‐induced invasiveness of kidney MDCKts‐src cells. In this model, MAGI‐1b slightly decreased the activity of AKT, a downstream effector of PI3K. By using dominant‐negative and constitutively active AKT expression vectors, we demonstrated that this kinase was included in the pathways involved in Src‐induced destabilization of junctional complexes and was necessary and sufficient to trigger invasiveness. We propose that the recruitment of PTEN at adherens junctions by MAGI‐1b and the local down‐regulation of phosphatidylinositol‐3,4,5‐trisphosphate pools and downstream effector systems at the site of cell‐cell contacts are focal points for restraining both disruption of junctional complexes and induction of tumor cell invasion.