Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling
Shuangshuang Zhong1, Huijing Yin1, Yueling Liao1
1Key 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.
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. ©2015 AACR.
Insights
Loss of GPRC5A, a lung tumor suppressor, promotes lung cancer by enhancing EGFR and STAT3 signaling. Restoring GPRC5A inhibits this signaling, offering a potential therapeutic strategy for lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- G-protein-coupled receptor family C group 5 member A (GPRC5A) is expressed in lung tissue but downregulated in lung cancers.
- Previous studies in Gprc5a knockout mice indicated a tumor-suppressive role for GPRC5A in lung cancer, but the underlying mechanisms were unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which GPRC5A suppresses lung tumorigenesis.
- To investigate the relationship between GPRC5A, epidermal growth factor receptor (EGFR) signaling, and signal transducer and activator of transcription 3 (STAT3) activation in lung cancer.
Main Methods:
- Utilized mouse tracheal epithelial cells (MTEC) from Gprc5a knockout and wild-type mice.
- Investigated physical interactions between GPRC5A and EGFR using biochemical assays.
- Assessed EGFR and STAT3 signaling pathways, cell proliferation, and response to EGFR inhibitors in GPRC5A-deficient and -expressing cells.
- Examined GPRC5A, EGFR, and STAT3 expression and signaling in Gprc5a knockout mouse lungs and human non-small cell lung carcinoma cells.
Main Results:
- GPRC5A functions as a negative modulator of EGFR signaling.
- Gprc5a knockout MTEC showed increased EGFR and STAT3 signaling compared to wild-type MTEC.
- GPRC5A physically interacts with EGFR, inhibiting its activity.
- Gprc5a knockout MTEC were more sensitive to EGFR inhibitors, indicating dependence on EGFR signaling.
- Dysregulated EGFR and STAT3 signaling were observed in Gprc5a knockout mouse lungs and tumors.
- EGFR inhibitor treatment reduced proliferation and signaling in Gprc5a knockout mouse lungs.
- Overexpression of GPRC5A in human lung cancer cells inhibited EGFR signaling.
Conclusions:
- GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling, promoting lung tumorigenesis.
- GPRC5A acts as a negative regulator of EGFR signaling, and its loss contributes to lung cancer development.
- Targeting EGFR signaling may be a viable therapeutic approach in lung cancers with GPRC5A deficiency.
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