GPR56/ADGRG1 induces biased Rho-ROCK-MLC and JAK-STAT3 signaling to promote amoeboid-like morphology and IL-6 upregulation in melanoma cells

Abstract

Abstract Background GPR56/ADGRG1 is an adhesion G protein-coupled receptor involved in cell-matrix interactions and metastasis of human melanoma cells. Previously, we demonstrated that GPR56 activation in melanoma cells triggers Gα12/13-RhoA signaling, leading to increased IL-6 production and enhanced cell migration. Yet little is known of the downstream signaling effectors and their specific roles in regulating melanoma cellular phenotypes. Results In this study, we show that GPR56 activation induces Rho-ROCK-MLC and JAK-STAT3 signaling, which temporally and differentially drive amoeboid-like morphology and IL-6 upregulation. Interestingly, GPR56-induced JAK-STAT3 activation is partially regulated by Rho-ROCK-MLC signaling but not vice versa. Moreover, receptor auto-proteolysis modulates the magnitude of GPR56-mediated signaling, and its unique intracellular regions contribute to the selective regulation of unique signaling pathways and associated cellular phenotypes. Conclusion Our findings reveal complex GPR56-mediated biased signaling through the Rho-ROCK-MLC and JAK-STAT3 pathways, highlighting these networks as potential therapeutic targets for modulating distinct tumorigenic phenotypes in human melanoma cells.

Keywords

• Adhesion GPCR
• IL-6
• Cytoskeletal remodelling
• GPR56
• Melanoma
• Signalling