Interactions between lysophosphatidylinositol receptor GPR55 and sphingosine-1-phosphate receptor S1P5 in live cells

• Published in: Biochemical and biophysical research communications 2021-09, Vol.570, p.53-59
• Main Authors: Hong, Hahoon, Yoon, Byoungsu, Ghil, Sungho
• Format: Article
• Language: English
• Subjects: Bioluminescence resonance energy transfer; Colon cancer; Crosstalk; Internalization
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.07.032

Lysophosphatidylinositol (LPI) and sphingosine-1-phosphate (S1P) are bioactive lipids implicated in various cellular events including proliferation, migration, and cancer progression. LPI and S1P act as ligands for G-protein coupled GPR55 and S1P receptors, respectively, and activate specific signaling pathways. Both receptors are highly expressed in various cancer tissues and associated with tumor progression. However, physical and functional crosstalk between the two receptors has not been elucidated to date. Bioluminescence resonance energy transfer (BRET) experiments in the current study showed that S1P5 strongly and specifically interacts with GPR55. We observed co-internalization of both receptors upon agonist stimulation. Notably, activation of one receptor induced co-internalization of the partner receptor. Next, we examined functional crosstalk of the two receptors. Interestingly, while activation of the individual receptors augmented cell proliferation, ERK phosphorylation and cancer-associated gene expression in HCT116 cells, co-activation of both receptors inhibited these stimulatory effects. Our collective findings indicate that GPR55 and S1P5 form a heterodimer and their co-activation attenuates the stimulatory activity of each receptor on colon cancer progression. •GPR55 interacts with S1P5 in live cells.•Both receptors are co-internalized by agonist stimulation.•Co-activation of both receptors inhibits the cellular effects of each receptor.•Our findings support physical and functional crosstalk between the two receptors.