A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells.
Accumulating evidence indicates that hyperactive Wnt signalling occurs in association with the development and progression of human breast cancer. As a consequence of engaging the canonical Wnt pathway, a beta-catenin-T-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelial-mesenchymal transition (EMT) that characterizes the tissue-invasive phenotype. However, the molecular mechanisms by which the beta-catenin-TCF complex induces EMT-like programmes remain undefined. Here, we demonstrate that canonical Wnt signalling engages tumour cell dedifferentiation and tissue-invasive activity through an Axin2-dependent pathway that stabilizes the Snail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by acting as a nucleocytoplasmic chaperone for GSK3beta, the dominant kinase responsible for controlling Snail1 protein turnover and activity. As dysregulated Wnt signalling marks a diverse array of cancerous tissue types, the identification of a beta-catenin-TCF-regulated Axin2-GSK3beta-Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.
Yook
Jong In
JI
Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry Yonsei University, Seoul 120-752, Korea.
Li
Xiao-Yan
XY
Ota
Ichiro
I
Hu
Casey
C
Kim
Hyun Sil
HS
Kim
Nam Hee
NH
Cha
So Young
SY
Ryu
Joo Kyung
JK
Choi
Yoon Jung
YJ
Kim
Jin
J
Fearon
Eric R
ER
Weiss
Stephen J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D002642:Chick Embryo; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D049790:Nuclear Export Signals; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C491761:AXIN2 protein, human; D060466:Axin Protein; D003598:Cytoskeletal Proteins; D049790:Nuclear Export Signals; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3