G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain. GPR56 is expressed in liver, muscle, tendon, neural, and cytotoxic lymphoid cells in human as well as in hematopoietic precursor, muscle, and developing neural cells in the mouse. GPR56 has been shown to have numerous role in cell guidance/adhesion as exemplified by its roles in tumour inhibition and neuron development. More recently it has been shown to be a marker for cytotoxic T cells and a subgroup of Natural killer cells. Ligands GPR56 binds transglutaminase 2 to suppress tumor metastasis and binds collagen III to regulate cortical development and lamination. Signaling GPR56 couples to Gαq/11 protein upon association with the tetraspanins CD9 and CD81. Forced GPR56 expression activates NF-kB, PAI-1, and TCF transcriptional response elements. The splicing of GPR56 induces tumorigenic responses as a result of activating the transcription of genes, such as COX2, iNOS, and VEGF85. GPR56 couples to the Gα12/13 protein and activates RhoA and mammalian target of rapamycin (mTOR) pathway upon ligand binding. Lack of the N-terminal fragment (NTF) of GPR56 causes stronger RhoA signaling and β-arrestin accumulation, leading to extensive ubiquitination of the C-terminal fragment (CTF). Finally, GPR56 suppresses PKCα activation to regulate angiogenesis. Function Studies in the hematopoietic system disclosed that during endothelial to hematopoietic stem cell transition, Gpr56 is a transcriptional target of the heptad complex of hematopoietic transcription factors, and is required for hematopoietic cluster formation. Recently, two studies showed that GPR56, is a cell autonomous regulator of oligodendrocyte development through Gα12/13 proteins and Rho activation. Della Chiesa et al. demonstrate that GPR56 is expressed on CD56dull natural killer (NK) cells. Lin and Hamann's group show all human cytotoxic lymphocytes, including CD56dull NK cells and CD27–CD45RA+ effector-type CD8+ T cells, express GPR56. Clinical significance GPR56 was the first adhesion GPCR causally linked to a disease. Loss-of-function mutations in GPR56 cause a severe cortical malformation known as bilateral frontoparietal polymicrogyria (BFPP). Investigating the pathological mechanism of disease-associated GPR56 mutations in BFPP has provided mechanistic insights into the functioning of adhesion GPCRs. Researchers demonstrated that disease-associated GPR56 mutations cause BFPP via multiple mechanisms. Li et al. demonstrated that GPR56