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 beta-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-kappa 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-kappa B and Akt activities but did not promote invasiveness or interfere with cell-cell aggregation. Intracellular delivery of competing peptides corresponding to TRIP6 or beta-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., Abdessamad, M., Kruglov, A., Bruyneel, E., Bracke, M., Di Gioia, Y., Beckerle, M. C., van Roy, F., Kotelevets, L. TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness. FASEB J. 23, 916-928 (2009)