Adhesion G-protein coupled receptor G1 (ADGRG1) (ADGRG1)

Adhesion G-protein coupled receptor G1 (ADGRG1), commonly known as GPR56, is a member of the adhesion GPCR family characterized by a large extracellular N-terminus and a GPCR-autoproteolysis inducing (GAIN) domain [1, 3]. It plays a critical role in brain development, specifically in cortical patterning, and its deficiency leads to bilateral frontoparietal polymicrogyria (BFPP), a severe malformation of the cerebral cortex [4, 9, 20]. Beyond the nervous system, GPR56 is involved in hematopoietic stem cell maintenance, muscle hypertrophy, and immune cell regulation, particularly as an inhibitory checkpoint for natural killer (NK) cells [1, 17]. In oncology, GPR56 exhibits a dual role: it acts as a tumor suppressor in melanoma by inhibiting metastasis through the regulation of the extracellular matrix, while it functions as an oncogene in colorectal cancer and glioblastoma, promoting cell proliferation and drug resistance [1, 11, 12]. Although no drugs are currently approved, GPR56 is an active area of research for the development of antidepressants and antibody-drug conjugates for cancer therapy [9, 11]. Experimental modulators include small molecule agonists like 3-alpha-DOG and monoclonal antibodies that target its unique activation mechanism involving a tethered peptide agonist [15, 16].

Other names

GPR56TM7XN1TM7LN4BFPPBPPRAdhesion G protein-coupled receptor G1

GPR56 signals primarily through the G12/13 and RhoA pathways, often triggered by the exposure of a tethered agonist peptide within the GAIN domain following mechanical force, ligand binding, or proteolytic cleavage [1, 15, 16, 19]. It also modulates PKC-alpha signaling in melanocytes and regulates the deposition of extracellular matrix components such as fibronectin and collagen III [2, 12].