Lung tumor suppressor GPRC5A binds EGFR and restrains its effector signaling
Menée à l'aide de modèles murins de cancer du poumon, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation EGFR, un récepteur couplé aux protéines G (GPRC5A) exerce une fonction de suppresseur de tumeurs
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 its the basis for its role have 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 EGRF inhibitory activity. Gprc5a-/- MTEC were much more susceptible to EGFR inhibitors than wile-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 EGRF and STAT3 activation along with cell proliferation. Lastly, 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.