GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis.

Jian Wang,Hong Yi,Hui-Kuo Shu,Duc M Duong,Ping Wang,Ya Wang,Kaiming Xu,Shi-Yong Sun,Xiangming Zhang,Alton B Farris

doi:10.1038/ncomms11795

Jian Wang, Hong Yi + Show 8 more

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https://doi.org/10.1038/ncomms11795

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Journal: Nature Communications	Publication Date: Jun 8, 2016
Citations: 26	License type: CC BY 4.0

Affiliation: Emory University, Emory and Henry College

Abstract

GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; however, the underlying mechanism remains unclear. Here we reveal that GPRC5A at the endoplasmic reticulum (ER) membrane suppresses synthesis of the secreted or membrane-bound proteins including a number of oncogenes, the most important one being Egfr. The ER-located GPRC5A disturbs the assembly of the eIF4F-mediated translation initiation complex on the mRNA cap through directly binding to the eIF4F complex with its two middle extracellular loops. Particularly, suppression of EGFR by GPRC5A contributes significantly to preventing ionizing radiation (IR)-induced lung tumorigenesis. Thus, GPRC5A deletion enhances IR-promoted EGFR expression through an increased translation rate, thereby significantly increasing lung tumour incidence in Gprc5a−/− mice. Our findings indicate that under-expressed GPRC5A during lung tumorigenesis enhances any transcriptional stimulation through an active translational status, which can be used to control oncogene expression and potentially the resulting related disease.

Highlights

GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; the underlying mechanism remains unclear
Since there is no evidence of a decrease in the protein expression level in the center of the distribution curve by western blot analysis in Gprc5a À / À lung bronchial epithelial (LBE) cells compared with equal cell numbers of wild-type LBE cells, we excluded the possibility of a global downregulation of proteins by GPRC5A deletion
The quantitative global proteomics data only includes a small portion of cell membrane proteins due to limitations in the approach, some cell membrane proteins in Gprc5a À / À LBE cells, such as Epidermal growth factor receptor (EGFR), Tmem[43], Cdh[1], and Itgb[4] and so on showed an extremely high expression, implying that GPRC5A might be involved in suppressing the cell membrane protein expression

Summary

Introduction

GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; the underlying mechanism remains unclear. Direct stimulation of EGFR by binding to a ligand, such as EGF, to the receptor’s extracellular domain leads to dimerization and subsequent autophosphorylation of two receptor molecules, thereby creating phosphotyrosine docking sites that activate intracellular signalling cascades. It is well known, based on mine workers and atomic bomb survivors[10,11], that ionizing radiation (IR) promotes lung tumorigenesis and abnormal EGFR is involved in radiation-stimulated lung cancers[12]; the whole picture needs to be elucidated. Deletion of Gprc5a significantly enhances IR-stimulated EGFR expression due to loss of translational suppression, thereby causing an increase in IR-induced lung tumour incidence

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