Oncotarget

Research Papers:

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER)

Shao Ma _, Ning Yin, Xiaomei Qi, Sandra L. Pfister, Mei-Jie Zhang, Rong Ma and Guan Chen

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Oncotarget. 2015; 6:13320-13333. https://doi.org/10.18632/oncotarget.3645

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Abstract

Shao Ma1,2, Ning Yin1, Xiaomei Qi1, Sandra L. Pfister1, Mei-Jie Zhang3, Rong Ma2, Guan Chen1,4

1Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

2Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong Province 250012, China

3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA

4Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53226, USA

Correspondence to:

Guan Chen, e-mail: gchen@mcw.edu

Rong Ma, e-mail: Malone@sdu.edu.cn

Keywords: protein tyrosine phosphatase H1 (PTPH1), EGFR, ER, protein-protein-interactions, therapeutic target activity

Received: February 14, 2015     Accepted: March 24, 2015     Published: April 10, 2015

ABSTRACT

Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.


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