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The proinvasive activity of Wnt‐2 is mediated through a noncanonical Wnt pathway coupled to GSK‐3β and c‐ Jun/AP‐1 signaling
Author(s) -
Le Floch Nathalie,
Rivat Christine,
De Wever Olivier,
Bruyneel Erik,
Mareel Marc,
Dale Trevor,
Gespach Christian
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2373fje
Subject(s) - wnt signaling pathway , gsk 3 , lrp5 , microbiology and biotechnology , chemistry , biology , signal transduction , catenin
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.