Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling.
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. ©2015 AACR.
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shuangshuang
S
Zhong
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Huijing
H
Yin
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yueling
Y
Liao
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Feng
F
Yao
Department of Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Qi
Q
Li
Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Jie
J
Zhang
Insitute of Health Science, Shanghai Institute of Biological Science, Chinese Academy of Science, Shanghai, China.
Huike
H
Jiao
Insitute of Health Science, Shanghai Institute of Biological Science, Chinese Academy of Science, Shanghai, China.
Yongxu
Y
Zhao
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Dongliang
D
Xu
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shuli
S
Liu
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Hongyong
H
Song
Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, China.
Yong
Y
Gao
Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky.
Jingyi
J
Liu
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Lina
L
Ma
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhi
Z
Pang
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ruixu
R
Yang
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Chengyi
C
Ding
Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Beibei
B
Sun
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xiaofeng
X
Lin
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xiaofeng
X
Ye
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Wenzheng
W
Guo
Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Baohui
B
Han
Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky. jiongdeng@shsmu.edu.cn peter.zhou@uky.edu yechin@sibs.ac.cn.
Binhua P
BP
Zhou
Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. Insitute of Health Science, Shanghai Institute of Biological Science, Chinese Academy of Science, Shanghai, China. jiongdeng@shsmu.edu.cn peter.zhou@uky.edu yechin@sibs.ac.cn.
Y Eugene
YE
Chin
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. jiongdeng@shsmu.edu.cn peter.zhou@uky.edu yechin@sibs.ac.cn.
Jiong
J
Deng
D000818:Animals; D055745:Bronchioles / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
C116760:GPRC5A protein, human; C554251:GPRC5A protein, mouse; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors