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

Abstract Background GPR56/ADGRG1 is an adhesion G protein-coupled receptor that plays a role in cell-matrix interaction and metastasis of human melanoma cells. We have shown previously that GPR56 activation in melanoma cells triggers Gα12/13-RhoA signaling to promote IL-6 production and cell migration. Yet little is known of the downstream signaling effectors and their roles in modulating melanoma cellular phenotypes. Results Here, we show that GPR56 activation induces Rho-ROCK-MLC and JAK-STAT3 signaling thereby temporally and differentially promoting amoeboid-like morphology and IL-6 upregulation. Interestingly, GPR56-induced JAK-STAT3 activation is modulated partly by Rho-ROCK-MLC signaling but not vice versa. Moreover, receptor auto-proteolysis is found to control the magnitude of GPR56-mediated signaling whereas its unique intracellular regions are involved in the differential regulation of selective signaling pathways and cellular phenotypes. Conclusion Our results uncover intricate GPR56-mediated biased Rho-ROCK-MLC and JAK-STAT3 signaling networks as potential therapeutic targets to regulate distinct tumorigenic phenotypes of human melanoma cells.