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

// Shao Ma 1, 2 , Ning Yin 1 , Xiaomei Qi 1 , Sandra L. Pfister 1 , Mei-Jie Zhang 3 , Rong Ma 2 , Guan Chen 1, 4 1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA 2 Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong Province 250012, China 3 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA 4 Zablocki 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.