Heparin interacts with adhesion-GPCR GPR56/ADGRG1, reduces receptor shedding, and promotes cell adhesion and motility

Abstract

GPR56 is an adhesion-class G protein-coupled receptor responsible for bilateral frontoparietal polymicrogyria (BFPP), a severe disorder of cortical formation. Additionally, GPR56 is involved in biological processes as diverse as hematopoietic stem cell generation and maintenance, myoblast fusion, muscle hypertrophy, immunoregulation, and tumorigenesis. Collagen III and tissue transglutaminase (TG2) were disclosed as the matricellular ligands of GPR56 involved in BFPP and melanoma development, respectively. In this study, we identify heparin as a glycosaminoglycan interacting partner of GPR56. Analyses of truncated and mutant GPR56 proteins denote two basic residue-rich clusters, R26GHREDFRFC35 and L190KHPQKASRRP200, as the major heparin-interacting motifs that overlap partially with the collagen III- and TG2-binding sites. Interestingly, GPR56-heparin interaction is modulated by collagen III but not TG2 even though both ligands are also heparin-binding proteins. Finally, we show that heparin interaction reduces GPR56 receptor shedding, and enhances cell adhesion and motility. These results provide novel insights into the interaction of GPR56 with its multiple endogenous ligands with functional implication in diseases such as BFPP and cancer.