ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1

Yihua Wang; Fangfang Bu; Christophe Royer; Sébastien Serres; James R. Larkin; Manuel Sarmiento Soto; Nicola R. Sibson; Victoria Salter; Florian Fritzsche; Casmir Turnquist; Sofia Koch; Jaroslav Zak; Shan Zhong; Guobin Wu; Anmin Liang; Patricia A. Olofsen; Holger Moch; David C. Hancock; Julian Downward; Robert D. Goldin; Jian Zhao; Xin Tong; Yajun Guo; Xin Lu

doi:10.1038/ncb3050

ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1

Yihua Wang, Fangfang Bu, Christophe Royer, Sébastien Serres, James R. Larkin, Manuel Sarmiento Soto, Nicola R. Sibson, Victoria Salter, Florian Fritzsche, Casmir Turnquist, Sofia Koch, Jaroslav Zak, Shan Zhong, Guobin Wu, Anmin Liang, Patricia A. Olofsen, Holger Moch, David C. Hancock, Julian Downward, Robert D. GoldinJian Zhao, Xin Tong, Yajun Guo^*, Xin Lu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 βL-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting βL-catenin's N-terminal phosphorylation to stabilize the βL-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 language	English
Pages (from-to)	1092-1104
Number of pages	13
Journal	Nature Cell Biology
Volume	16
Issue number	11
DOIs	https://doi.org/10.1038/ncb3050
Publication status	Published - 31 Oct 2014
Externally published	Yes

Access to Document

10.1038/ncb3050

Cite this

Wang, Y., Bu, F., Royer, C., Serres, S., Larkin, J. R., Soto, M. S., Sibson, N. R., Salter, V., Fritzsche, F., Turnquist, C., Koch, S., Zak, J., Zhong, S., Wu, G., Liang, A., Olofsen, P. A., Moch, H., Hancock, D. C., Downward, J., ... Lu, X. (2014). ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1. Nature Cell Biology, 16(11), 1092-1104. https://doi.org/10.1038/ncb3050

@article{5a78b33604504a4f9970d38f7b104a76,

title = "ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1",

abstract = "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 βL-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting βL-catenin's N-terminal phosphorylation to stabilize the βL-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.",

author = "Yihua Wang and Fangfang Bu and Christophe Royer and S{\'e}bastien Serres and Larkin, {James R.} and Soto, {Manuel Sarmiento} and Sibson, {Nicola R.} and Victoria Salter and Florian Fritzsche and Casmir Turnquist and Sofia Koch and Jaroslav Zak and Shan Zhong and Guobin Wu and Anmin Liang and Olofsen, {Patricia A.} and Holger Moch and Hancock, {David C.} and Julian Downward and Goldin, {Robert D.} and Jian Zhao and Xin Tong and Yajun Guo and Xin Lu",

year = "2014",

month = oct,

day = "31",

doi = "10.1038/ncb3050",

language = "English",

volume = "16",

pages = "1092--1104",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "11",

}

Wang, Y, Bu, F, Royer, C, Serres, S, Larkin, JR, Soto, MS, Sibson, NR, Salter, V, Fritzsche, F, Turnquist, C, Koch, S, Zak, J, Zhong, S, Wu, G, Liang, A, Olofsen, PA, Moch, H, Hancock, DC, Downward, J, Goldin, RD, Zhao, J, Tong, X, Guo, Y & Lu, X 2014, 'ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1', Nature Cell Biology, vol. 16, no. 11, pp. 1092-1104. https://doi.org/10.1038/ncb3050

TY - JOUR

T1 - ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1

AU - Wang, Yihua

AU - Bu, Fangfang

AU - Royer, Christophe

AU - Serres, Sébastien

AU - Larkin, James R.

AU - Soto, Manuel Sarmiento

AU - Sibson, Nicola R.

AU - Salter, Victoria

AU - Fritzsche, Florian

AU - Turnquist, Casmir

AU - Koch, Sofia

AU - Zak, Jaroslav

AU - Zhong, Shan

AU - Wu, Guobin

AU - Liang, Anmin

AU - Olofsen, Patricia A.

AU - Moch, Holger

AU - Hancock, David C.

AU - Downward, Julian

AU - Goldin, Robert D.

AU - Zhao, Jian

AU - Tong, Xin

AU - Guo, Yajun

AU - Lu, Xin

PY - 2014/10/31

Y1 - 2014/10/31

N2 - 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 βL-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting βL-catenin's N-terminal phosphorylation to stabilize the βL-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.

AB - 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 βL-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting βL-catenin's N-terminal phosphorylation to stabilize the βL-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.

UR - http://www.scopus.com/inward/record.url?scp=84908479373&partnerID=8YFLogxK

U2 - 10.1038/ncb3050

DO - 10.1038/ncb3050

M3 - Article

C2 - 25344754

AN - SCOPUS:84908479373

SN - 1465-7392

VL - 16

SP - 1092

EP - 1104

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 11

ER -

ASPP2 controls epithelial plasticity and inhibits metastasis through β 2-catenin-dependent regulation of ZEB1

Abstract

Access to Document

Other files and links

Fingerprint

Cite this