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

ASPP2 controls epithelial plasticity and inhibits metastasis through ?-catenin-dependent regulation of ZEB1
ASPP2 controls epithelial plasticity and inhibits metastasis through ?-catenin-dependent regulation of ZEB1
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 ??-catenin from transactivating ?ZEB1, directly by forming an ?ASPP2–??-catenin–?E-cadherin ternary complex and indirectly by inhibiting ??-catenin’s N-terminal phosphorylation to stabilize the ??-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.
cancer, cell invasion, metastasis
1465-7392
1092-1104
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Bu, Fangfang
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Royer, Christophe
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Serres, Sébastien
f1696c3f-0627-4483-9905-df20c9bea4eb
Larkin, James R.
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Soto, Manuel Sarmiento
494c7ed0-28c9-4bfc-878f-41bbe51bfed7
Sibson, Nicola R.
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Salter, Victoria
66a182c2-e71a-4b8e-a649-add7d7ea92e1
Fritzsche, Florian
e1007ab2-f7df-4425-9326-84a8c85666d1
Turnquist, Casmir
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Koch, Sofia
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Zak, Jaroslav
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Zhong, Shan
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Wu, Guobin
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Liang, Anmin
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Olofsen, Patricia A.
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Moch, Holger
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Hancock, David C.
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Downward, Julian
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Goldin, Robert D.
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Zhao, Jian
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Tong, Xin
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Guo, Yajun
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Lu, Xin
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Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Bu, Fangfang
3fc9edbb-ba30-4f34-8a9c-4db06cbb32cd
Royer, Christophe
6f928270-64ef-42ba-9a6b-ebb4d8403a3a
Serres, Sébastien
f1696c3f-0627-4483-9905-df20c9bea4eb
Larkin, James R.
021c7d55-27a6-48a7-bad0-03e09b3417b2
Soto, Manuel Sarmiento
494c7ed0-28c9-4bfc-878f-41bbe51bfed7
Sibson, Nicola R.
408b5626-2da8-4fc8-9fb5-bbe52a7b8aaf
Salter, Victoria
66a182c2-e71a-4b8e-a649-add7d7ea92e1
Fritzsche, Florian
e1007ab2-f7df-4425-9326-84a8c85666d1
Turnquist, Casmir
b186b838-ec0f-48f7-8ec3-ed9a56adb592
Koch, Sofia
dae4f993-c866-4348-9eed-a0a9ac738ed1
Zak, Jaroslav
4dbe4260-3c95-433d-b465-5aa35e6ed3f2
Zhong, Shan
6d0d5d48-c69b-444d-acae-fd7a3fd76e23
Wu, Guobin
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Liang, Anmin
f6f006a2-423e-4759-8513-dba72b3dd931
Olofsen, Patricia A.
af86eb79-041c-4b90-937e-2bf300d63c59
Moch, Holger
b7b64874-fe15-44a3-a184-12a8180a377a
Hancock, David C.
cc232284-a0d9-499d-af40-8ab6e08139b7
Downward, Julian
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Goldin, Robert D.
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Zhao, Jian
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Tong, Xin
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Guo, Yajun
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Lu, Xin
a681bac0-d6d1-4e8e-a642-4ce42ae2cc9d

Wang, Yihua, Bu, Fangfang, Royer, Christophe, Serres, Sébastien, Larkin, James R., Soto, Manuel Sarmiento, Sibson, Nicola R., Salter, Victoria, Fritzsche, Florian, Turnquist, Casmir, Koch, Sofia, Zak, Jaroslav, Zhong, Shan, Wu, Guobin, Liang, Anmin, Olofsen, Patricia A., Moch, Holger, Hancock, David C., Downward, Julian, Goldin, Robert D., Zhao, Jian, Tong, Xin, Guo, Yajun and Lu, Xin (2014) ASPP2 controls epithelial plasticity and inhibits metastasis through ?-catenin-dependent regulation of ZEB1. Nature Cell Biology, 16 (11), 1092-1104. (doi:10.1038/ncb3050).

Record type: Article

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 ??-catenin from transactivating ?ZEB1, directly by forming an ?ASPP2–??-catenin–?E-cadherin ternary complex and indirectly by inhibiting ??-catenin’s N-terminal phosphorylation to stabilize the ??-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.

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More information

Accepted/In Press date: 10 September 2014
e-pub ahead of print date: 26 October 2014
Published date: November 2014
Keywords: cancer, cell invasion, metastasis
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 385898
URI: http://eprints.soton.ac.uk/id/eprint/385898
ISSN: 1465-7392
PURE UUID: 25ef472d-9da6-46c6-8e5d-f841261bea8b
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 26 Jan 2016 08:57
Last modified: 03 Dec 2019 01:33

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Contributors

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

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