Chaperone gp96 mediates ER-α36 cell membrane expression
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Junwei Hou1, Mengmeng Deng1, Xin Li1, Weiwei Liu1, Xiaoyu Chu1, Jing Wang2, Feng Chen2, Songdong Meng1
1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, P.R. China
2Shenogen Pharma Group, Changping District, Beijing 102206, P.R. China
Songdong Meng, e-mail: firstname.lastname@example.org
Feng Chen, e-mail: email@example.com
Keywords: ER-α36, gp96, ubiquitin, MAPK, breast cancer
Received: April 26, 2015 Accepted: August 28, 2015 Published: September 10, 2015
ER (estrogen receptor)-α36, a variant of human ERα, activates non-genomic cell signaling pathways. ER-α36 on the cell membrane plays a role in breast cancer growth and development, and contributes to tamoxifen resistance. However, it is not understood how cell membrane expression of ER-α36 is regulated. In this study, we investigated the role of cell membrane glycoprotein 96 (mgp96) in the regulation of ER-α36 expression and signaling. We found that the C-terminal domain of mgp96 directly interacts with ER-α36 on the cell membrane of breast tumor cells. This interaction stabilizes the ER-α36 protein, thereby increasing its signaling, which, in turn, increases tumor cell growth and invasion. Moreover, targeting mgp96 with siRNA or monoclonal antibody (mAb) blocks the mgp96-ER-α36 interaction and inhibits breast cancer growth and invasion both in vitro and in vivo. These results provide insights into the modulation of cell membrane ER-α36 expression and suggest that mgp96 could be a potential therapeutic target for ER-α36-overexpressing breast cancer.
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