Adhesion G protein-coupled receptor G1 (GPR56) (ADGRG1)

Adhesion G protein-coupled receptor G1 (ADGRG1), widely known as GPR56, is a member of the adhesion GPCR family characterized by a large N-terminal extracellular region and a GPCR-autoproteolysis inducing (GAIN) domain (UniProt, 2.1.2). It plays a critical role in central nervous system development, particularly in cortical lamination and the regulation of oligodendrocyte-mediated myelination (NIH, 2.1.5). Mutations in the ADGRG1 gene are the primary cause of bilateral frontoparietal polymicrogyria (BFPP), a severe brain malformation (Wikipedia, 2.1.1). Beyond the brain, GPR56 is involved in immune cell regulation, muscle hypertrophy, and pancreatic beta-cell function, where it modulates insulin secretion (NIH, 2.2.1). In oncology, GPR56 exhibits a dual role: it acts as a tumor suppressor in melanoma by inhibiting metastasis through interactions with transglutaminase 2, but it is frequently upregulated and promotes progression in glioblastoma and colorectal cancer (NIH, 2.1.4, 2.4.2). This high expression in specific cancers makes it an attractive target for antibody-drug conjugates (ADCs) and small-molecule modulators (bioRxiv, 3.1.1). Current pharmacological research focuses on its unique "tethered agonist" activation mechanism, where the N-terminal fragment is shed to reveal a signaling peptide (Molecular Pharmacology, 3.2.1). While no GPR56-targeted drugs are currently approved, several small-molecule agonists and monoclonal antibodies are in preclinical development for cancer and neurological applications (Guide to Pharmacology, 3.3.3).

Other names

GPR56TM7XN1BFPPBPPRTM7LN4G protein-coupled receptor 56

Agonism, Antagonism, Antibody-drug conjugate (ADC) internalization, Tethered agonist activation (Stachel peptide unmasking)