Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway

  • Cell Death Dis. 2020 Aug 27;11(8):709. doi: 10.1038/s41419-020-02831-0.
Yi-Ping Xiang  1  2  3 ,  Ta Xiao  4 ,  Qi-Guang Li  2  3 ,  Shan-Shan Lu  2  4 ,  Wei Zhu  2  3 ,  Yun-Ya Liu  2  3 ,  Jie-Ya Qiu  2  3 ,  Zheng-Hui Song  2  3 ,  Wei Huang  2  3 ,  Hong Yi  2  3 ,  Yao-Yun Tang  1 ,  Zhi-Qiang Xiao  5  6  7
Affiliations
  • 1. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 2. Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 3. The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 4. Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China.
  • 5. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China. [email protected].
  • 6. Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China. [email protected].
  • 7. The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China. [email protected].
PMID: 32848131 DOI: 10.1038/s41419-020-02831-0
Abstract

EphA2 is an important oncogenic protein and emerging drug target, but the oncogenic role and mechanism of ligand-independent phosphorylation of EphA2 at tyrosine 772 (pY772-EphA2) is unclear. In this study, we established nasopharyngeal carcinoma (NPC) cell lines with stable expression of exogenous EphA2 and EphA2-Y772A (phosphorylation inactivation) using endogenous EphA2-knockdown cells, and observed that pY772A EphA2 was responsible for EphA2-promoting NPC cell proliferation and anchorage-independent and in vivo growth in mice. Mechanistically, EphA2-Y772A mediated EphA2-activating SHP2/Erk-1/2 signaling pathway in the NPC cells, and Gab1 (Grb2-associated binder 1) and Grb2 (growth factor receptor-bound protein 2) were involved in pY772-EphA2 activating this signaling pathway. Our results further showed that SHP2/Erk-1/2 signaling mediated pY772-EphA2-promoting NPC cell proliferation and anchorage-independent growth. Moreover, we observed that EphA2 tyrosine kinase inhibitor ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation. Collectively, our results demonstrate that pY772-EphA2 is responsible for EphA2-dependent NPC cell growth in vitro and in vivo by activating SHP2/Erk-1/2 signaling pathway, and is a pharmacologic target of ALW-II-41-27, suggesting that pY772-EphA2 can serve as a therapeutic target in NPC and perhaps in Other cancers.

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