Lung tumor suppressor GPRC5A binds EGFR and restrains its effector signaling

Shuangshuang Zhong, Huijing Yin, Yueling Liao, Feng Yao, Qi Li, Jie Zhang, Huike Jiao, Yongxu Zhao, Dongliang Xu, Shuli Liu, Hongyong Song, Yong Gao, Jingyi Liu, Lina Ma, Zhi Pang, Ruixu Yang, Chengyi Ding, Beibei Sun, Xiaofeng Lin, Xiaofeng YeWenzheng Guo, Baohui Han, Binhua P. Zhou, Y. Eugene Chin, Jiong Deng

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

GPRC5A is a G-protein-coupled receptor expressed in lung tissue but repressed in most human lung cancers. Studies in Gprc5a-/- mice have established its role as a tumor-suppressor function in this setting, but the basis for its role has been obscure. Here, we report that GPRC5A functions as a negative modulator of EGFR signaling. Mouse tracheal epithelial cells (MTEC) from Gprc5a-/- mice exhibited a relative increase in EGFR and downstream STAT3 signaling, whereas GPRC5A expression inhibited EGFR and STAT3 signaling. GPRC5A physically interacted with EGFR through its transmembrane domain, which was required for its EGFR inhibitory activity. Gprc5a-/- MTEC were much more susceptible to EGFR inhibitors than wild-type MTEC, suggesting their dependence on EGFR signaling for proliferation and survival. Dysregulated EGFR and STAT3 were identified in the normal epithelia of small and terminal bronchioles as well as tumors of Gprc5a-/- mouse lungs. Moreover, in these lungs EGFR inhibitor treatment inhibited EGFR and STAT3 activation along with cell proliferation. Finally, overexpression of ectopic GPRC5A in human non-small cell lung carcinoma cells inhibited both EGF-induced and constitutively activated EGFR signaling. Taken together, our results show how GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling and lung tumorigenesis. Cancer Res; 75(9); 1801-14.

Original languageEnglish
Pages (from-to)1801-1814
Number of pages14
JournalCancer Research
Volume75
Issue number9
DOIs
StatePublished - May 1 2015

Bibliographical note

Publisher Copyright:
© 2015 AACR.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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