The Adhesion G Protein-Coupled Receptor GPR56/ADGRG1 Is an Inhibitory Receptor on Human NK Cells

Abstract

Natural killer (NK) cells possess potent cytotoxic mechanisms that need to be tightly controlled. Here, we explored the regulation and function of GPR56/ADGRG1, an adhesion G protein-coupled receptor implicated in developmental processes and expressed distinctively in mature NK cells. Expression of GPR56 was triggered by Hobit (a homolog of Blimp-1 in T cells) and declined upon cell activation. Through studying NK cells from polymicrogyria patients with disease-causing mutations in ADGRG1, encoding GPR56, and NK-92 cells ectopically expressing the receptor, we found that GPR56 negatively regulates immediate effector functions, including production of inflammatory cytokines and cytolytic proteins, degranulation, and target cell killing. GPR56 pursues this activity by associating with the tetraspanin CD81. We conclude that GPR56 inhibits natural cytotoxicity of human NK cells.

Activation of Adhesion GPCR EMR2/ADGRE2 Induces Macrophage Differentiation and Inflammatory Responses via Gα16/Akt/MAPK/NF-κB Signaling Pathways

“…In brief, cells were harvested by centrifugation at 1,500 rpm for 5 min at 4°C, washed once with ice-cold 1× HBSS, and lysed in 100-µl ice-cold modified cell lysis buffer as described previously (29). Proteins were quantified using Bicinchoninic acid protein assay kit (PIERCE, Rockford, IL, USA) by reading absorbance at 550 nm.…”

Progressive change in expression of killer-like receptorsr and GPR56 expression defines the cytokine production potential of human CD4+ T memory cells

“…GPR56 was shown to be expressed by cytotoxic NK and T lymphocytes including CD8 + , CD4 + and gd + T cells (41). For NK cells an inhibitory role for GPR56 in controlling steady state activation by associating with the tetraspanin CD81 was revealed (52). Similar to KLRF1, the role of GPR56 for stimulation-dependent production of cytokines by human CD4 + T cells is unknown and needs to be investigated in further studies.…”

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

“…For example, the aGPCR GPR56/ADGRG1 is involved in cortex development, oligodendrocyte development, muscle cell development, innate immunity, and cancer progression (11)(12)(13)(14)(15)(16)(17). Recent studies have highlighted the role of GPR56 in promoting progression of acute myeloid leukemia (18) and progastrin-dependent colon cancer (19) and suggested that a GPR56 inhibitor would be clinically desirable.…”