Wnt Signaling Stabilizes Snail Via the Ax in2-Reg 비 ated Control of GSK3 Compartmental ization
pp.125-126
Down-regulation of E-cadherin marks the initiation of the epithelial-mesenchymal transit ion (EMT), a process exploited by cancer cells that display an invasive phenotype. The zinc finger transcription factor , Snail , functions as a potent repressor of E-cadherin expression that can, acting alone or in concert with the Wnt/β -catenin/TCFaxis, induce EMT both in neoplastic cells as well as normal cells during embryonic development. While mechanisms that might coordinate signaling events initiated by Snail and Wnt remain undefined, it is demonstrated that Snail displays ß -catenin-like canonical motifs that support its GS3Kdepende nt phosphorylation, ß - TrCP-directed ubiquitination and proteasomal degradation. Accordingly, Snail half- life and repressor activity is enhanced by constructingphosphorylation- res istant mutants, depressing GSK3 activity via the Wnt signaling cascade or inhibiting proteasome function These findings define a potential mechanism wher eby Wnt signaling stabilizes the intracellular Snail and ß -catenin in tandem so as to cooperati vely engage the transcriptional programs that control EMT 1n human cancer, hyperactive Wnt signaling leads to the formation of a bipartite, -catenin/T ce ll facto r (TCF) complex which has been postulated to serγe as a trigger of the EMT that characterizes the tissue-invasive and metastatic properties of cancer cells. However, the molecular mechani sms by whi ch the ß -catenin/TCF complex triggers EMT-like programs remain undefined. Herein, it will be demonstrate that canonical Wnt signaling engages tumor cell de-differentiation and tissue-invasive activity by a heretofore unsuspected Axin2-dependent pathway that serves to stabilize the zinc transcription factor, Snail - a key regulator of normal and neoplastic EMT programs. Axin2 exerts this effect by acting as a nucleocytoplasmic chaperone for GSK3, the dominant kinase responsible for controlling Snail phosphorylation, ubiquitination and proteosomal degradation. As dysregulated Wnt signaling marks a diverse array of carcinogenic and metastatic states, t he identification of a ß -catenin/TCF-regulated Axin2/GSK3/Snail1 axis provides new mechanistic insights into Wnt- mediated EMT programs of human cancer