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Epithelial to mesenchymal transition (EMT), and the reverse mesenchymal to epithelial transition (MET), are known examples of epithelial plasticity that are important in kidney development and cancer metastasis. Here we identify ASPP2, a haploinsufficient tumour suppressor, p53 activator and PAR3 binding partner, as a molecular switch of MET and EMT. ASPP2 contributes to MET in mouse kidney in vivo. Mechanistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin's N-terminal phosphorylation to stabilize the β-catenin-E-cadherin complex. ASPP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASPP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients. Hence, ASPP2 is a key regulator of epithelial plasticity that connects cell polarity to the suppression of WNT signalling, EMT and tumour metastasis.

Original publication

DOI

10.1038/ncb3050

Type

Journal article

Journal

Nature cell biology

Publication Date

11/2014

Volume

16

Pages

1092 - 1104

Addresses

Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.

Keywords

Cell Line, Tumor, Animals, Humans, Mice, Neoplasm Metastasis, Homeodomain Proteins, Tumor Suppressor Proteins, Transcription Factors, Gene Expression Regulation, Neoplastic, Phosphorylation, Apoptosis Regulatory Proteins, beta Catenin, Kruppel-Like Transcription Factors, Epithelial-Mesenchymal Transition, Wnt Signaling Pathway, Zinc Finger E-box-Binding Homeobox 1