Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
1] International Joint Cancer Institute &Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai 200433, China [2] PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, 28 Fuxing Road Beijing 100853, China.
Nat Cell Biol. 2014 Nov;16(11):1092-104. doi: 10.1038/ncb3050. Epub 2014 Oct 26.
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.
上皮间质转化（EMT）和相反的间质上皮转化（MET）是上皮可塑性的已知范例，在肾脏发育和癌症转移中很重要。在这里，我们确定了 ASPP2，一种单倍不足的肿瘤抑制因子、p53 激活剂和 PAR3 结合伴侣，作为 MET 和 EMT 的分子开关。ASPP2 有助于体内小鼠肾脏的 MET。在机制上，ASPP2 通过其 PAR3 结合的氨基末端独立于 p53 结合诱导 MET。ASPP2 通过形成 ASPP2-β-连环蛋白-E-钙黏蛋白三元复合物，以及通过抑制 β-连环蛋白的 N 端磷酸化来稳定 β-连环蛋白-E-钙黏蛋白复合物，直接阻止β-连环蛋白转录激活 ZEB1。ASPP2 限制致癌 RAS 的促侵袭特性并抑制体内肿瘤转移。ASPP2 表达减少导致 EMT，并与肝癌和乳腺癌患者的不良生存相关。因此，ASPP2 是连接细胞极性与 WNT 信号通路、EMT 和肿瘤转移抑制的上皮可塑性的关键调节剂。
