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-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.
Chastre
Eric
E
INSERM U773, Université Paris 7, Paris, France. eric.chastre@inserm.fr
Abdessamad
Mahmoud
M
Kruglov
Alexey
A
Bruyneel
Erik
E
Bracke
Marc
M
Di Gioia
Yolande
Y
Beckerle
Mary C
MC
van Roy
Frans
F
Kotelevets
Larissa
L
D000074183:ATPases Associated with Diverse Cellular Activities; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D051528:Guanylate Kinases; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D060588:LIM Domain Proteins; D016328:NF-kappa B; C092282:PSMC5 protein, human; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D051528:Guanylate Kinases; C113338:MAGI1 protein, human; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; D020741:rho GTP-Binding Proteins