Anghel, S. A.; Badea, R. A.; Trif, C.; Stratulat, T.; Trita, C.; Navligu, D. G.; Petrescu, S. M.; Babes, A.; Popescu, C. I.; Coman, C.; Hanson, J.; Tunaru, S.

G-protein coupled receptor 27 (GPR27) is part of the Super Conserved Receptors Expressed in Brain (SREB) family, alongside GPR85 and GPR173. While the endogenous ligands and functions of SREB receptors are still unknown, GPR27 has been implicated in insulin secretion and tumorigenesis. Here, we show that substituting GPR27\' C-terminus domain with that of the {beta}-1 adrenergic receptor (1AR) yields a chimera with {beta}-1AR-like ligand selectivity and cellular functions. Interestingly, adrenergic ligands stimulation of GPR27 inhibited EGF-induced serum-responsive element (SRE) activation, independently of G-proteins and beta-arrestins, through dephosphorylation of c-Src and EGFR proteins. This unique response was exclusive to GPR27, as GPR85 and GPR173 showed no similar effects. These findings suggest that GPR27 is a receptor responding to adrenergic ligands to transinhibit EGFR through an atypical signaling mechanism.