TRIP6, a novel molecular partner of the MAGI‐1 scaffolding molecule, promotes invasiveness

We recently established the critical role of the PTEN/MAGI-1b signalosome in stabilization of cell-cell contacts and suppression of invasiveness.The PTEN tumor suppressor is recruited to E-cadherin junctional complexes through the binding to the second PDZ domain of the MAGI-1b scaffolding molecule, whereas ␤-catenin interacts with the fifth PDZ domain.To identify additional effectors of this signalosome, we used yeast 2-hybrid screening.Among the clones identified, we focused on TRIP6, which belongs to the zyxin family of proteins.We demonstrated that TRIP6 interacted directly with MAGI-1b by binding to its fifth PDZ domain.Ectopic expression of TRIP6 induced invasiveness in the epithelial MDCK and MDCKts-src cells in a PI3-kinase-and a NF-B-dependent manner and impaired cell-cell aggregation at least in part by uncoupling adherens junctional complexes from the cytoskeleton.The TRIP6Stop473 mutant, which lacks the PDZ binding motif, was still able to increase NF-B and Akt activities but did not promote invasiveness or interfere with cell-cell aggregation.Intracellular delivery of competing peptides corresponding to TRIP6 or ␤-catenin C terminus restored invasive properties in MDCKts-src TRIP6Stop473 cells, highlighting the requirement of PDZ scaffolds in junctional complexes activity.TRIP6 overexpression in colon tumors suggest its critical role in cancer progression.-Chastre,E.,