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The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3  and c-Jun/AP-1 signaling

Le Floch, N., Rivat, C., De Wever, O., Bruyneel, E., Mareel, M., Dale, Trevor Clive ORCID: and Gespach, C. 2005. The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3  and c-Jun/AP-1 signaling. The FASEB Journal 19 (1) , pp. 144-146. 10.1096/fj.04-2373fje

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Inappropriate activation of the Wnt/APC/β-catenin signaling pathways plays a critical role at early stages in a variety of human cancers. However, their respective implication in tumor cell invasion is still hypothetical. Here, we show that two activators of the canonical Wnt/β-catenin transcription pathway, namely Dvl-2, the Axin 501–560 fragment binding glycogen synthase kinase -3β (GSK-3β), and the negative Wnt regulator wt-Axin did not alter cell invasion into type I collagen. In addition, both Dvl-2 and Axin 501–560 exerted a permissive action on the proinvasive activity of HGF and intestinal trefoil factor. Upstream activation of Wnt signaling by the Wnt-2 and Wnt-3a ligands, stable overexpression of Wnt-2, as well as GSK-3β inhibition by lithium, SB216763, and GSK-3β dominant negative forms (K85R and R96E) conferred the invasive phenotype through several proinvasive pathways. Induction of the matrix metalloprotease MMP-7 (matrilysin) gene and protein by Wnt-2 was abolished by inactivation of the AP-1 binding site in the promoter. Accordingly, invasion induced by Wnt-2 was prevented by soluble FRP-3 and FRP-1, sequestration of Gβγ subunits, depletion of the GSK-3β protein by RNA interference, the c-Jun dominant negative mutant TAM67 and was not reversed by wt- Axin. Thus, the proinvasive activity of Wnt-2 is mediated by a noncanonical Wnt pathway using GSK-3β and the AP-1 oncogene. Our data provide a potential clue for our understanding of the action and crosstalk between Wnt activators and other proinvasive pathways, in relation with matrix substrates and proteases in human cancers.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: Federation of American Society of Experimental Biology
ISSN: 0892-6638
Funders: Cancer Research UK
Last Modified: 22 Jun 2023 10:01

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