Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

Xiangyang Xiong; Yao Wang; Chengmei Liu; Quqin Lu; Tao Liu; Guoan Chen; Hai Rao; Shiwen Luo

doi:10.1016/j.yexcr.2014.05.018

Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

Xiangyang Xiong, Yao Wang, Chengmei Liu, Quqin Lu, Tao Liu, Guoan Chen, Hai Rao, Shiwen Luo

Department of Molecular Medicine

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

24 Scopus citations

Abstract

Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233-620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer.

Original language	English (US)
Pages (from-to)	78-89
Number of pages	12
Journal	Experimental Cell Research
Volume	326
Issue number	1
DOIs	https://doi.org/10.1016/j.yexcr.2014.05.018
State	Published - Aug 1 2014

Keywords

Breast cancer
FAK
HSP90β
Metastasis
Ubiquitin

ASJC Scopus subject areas

Cell Biology

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10.1016/j.yexcr.2014.05.018

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title = "Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells",

abstract = "Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233-620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer.",

keywords = "Breast cancer, FAK, HSP90β, Metastasis, Ubiquitin",

author = "Xiangyang Xiong and Yao Wang and Chengmei Liu and Quqin Lu and Tao Liu and Guoan Chen and Hai Rao and Shiwen Luo",

note = "Funding Information: We thank Dr. Subrata Haldar (University of Texas) for editorial assistance of this manuscript, Dr. Lin Mei (Georgia Regents University) for HSP90 constracts, Dr. Zhijun Luo (Nanchang University) for reagents and Ms. Lingfang Wang for assistance with imaging analysis. This work was supported in part by grants from the China National Basic Research Program ( 2010CB535001 ), the National Natural Science Foundation of China ( 81060095 , 31171359 ), the Program of International S&T Cooperation Projects of China ( 010S2012ZR02 ), the Natural Science Foundation of Jiangxi Province ( 20114BAB205035 and 20132BAB205109 ) and the NIH ( P30 CA054174 ). ",

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T1 - Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

AU - Xiong, Xiangyang

AU - Wang, Yao

AU - Liu, Chengmei

AU - Lu, Quqin

AU - Liu, Tao

AU - Chen, Guoan

AU - Rao, Hai

AU - Luo, Shiwen

N1 - Funding Information: We thank Dr. Subrata Haldar (University of Texas) for editorial assistance of this manuscript, Dr. Lin Mei (Georgia Regents University) for HSP90 constracts, Dr. Zhijun Luo (Nanchang University) for reagents and Ms. Lingfang Wang for assistance with imaging analysis. This work was supported in part by grants from the China National Basic Research Program ( 2010CB535001 ), the National Natural Science Foundation of China ( 81060095 , 31171359 ), the Program of International S&T Cooperation Projects of China ( 010S2012ZR02 ), the Natural Science Foundation of Jiangxi Province ( 20114BAB205035 and 20132BAB205109 ) and the NIH ( P30 CA054174 ).

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233-620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer.

AB - Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233-620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer.

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KW - Metastasis

KW - Ubiquitin

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Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

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