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

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作   者：

Chastre E;  Abdessamad M;  Kruglov A;  Bruyneel E;  Bracke M;  Di-Gioia Y;  Beckerle MC;  van-Roy F;  Kotelevets L; 

作者机构：

France. eric.chastre@inserm.fr;  INSERM U773;  Paris;  Universite Paris 7; 

关键词：

Molecule;  细胞;  binding;  Cells;  novel;  Not free of; 

期刊名称：

The FASEB Journal

i s s n：

0892-6638

年卷期：

2009 年 23 卷 3 期

页   码：

916-928

页   码：

摘   要：

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-kappaB-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-kappaB 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.