GPR56, also known as ADGRG1, is a protein found on the surface of cells throughout the body. It belongs to a large family of proteins called G protein-coupled receptors (GPCRs), which are involved in various bodily functions. While GPCRs typically receive signals and transmit them inside the cell, GPR56 stands out as an “adhesion GPCR” due to its role in cell-to-cell communication and adhesion. This protein plays diverse roles in human health, from brain development to immune regulation and the progression of certain diseases.
How GPR56 Works
GPR56 functions as a receptor, receiving signals from outside a cell and relaying them inward to influence cell behavior. As an adhesion GPCR, it has a large extracellular region, often with protein modules at its N-terminal end. This region connects to a seven-transmembrane (7TM) domain via a unique structure called the GPCR-Autoproteolysis INducing (GAIN) domain.
The GAIN domain is responsible for an auto-proteolytic process, where the receptor cleaves itself into two fragments: an N-terminal fragment (NTF) and a C-terminal fragment (CTF). GPR56 interacts with other proteins on the cell surface to initiate chemical signals inside the cell. These interactions influence cell adhesion to one another and to their surrounding environment, the extracellular matrix (ECM).
GPR56’s Role in Brain Development
GPR56 plays a significant role in the developing brain, particularly in neuronal migration. Neuronal migration is the precise movement of nerve cells from their birthplace to their correct locations, fundamental for healthy brain structure and function. In the developing cerebral cortex, GPR56 is expressed in neuronal progenitor cells, the precursors to nerve cells.
Collagen III has been identified as a ligand for GPR56. When GPR56 binds to collagen III, it activates a signaling pathway involving proteins like RhoA through coupling with Gα12/13 proteins. This pathway is important in preplate neurons.
If GPR56 function is impaired, it can lead to severe brain malformations, such as bilateral frontoparietal polymicrogyria (BFPP). This condition is characterized by an abnormally folded cerebral cortex with too many small folds, resulting from disruptions in neuronal migration. Mutations in the ADGRG1 gene, which encodes GPR56, interfere with the protein’s normal processing, preventing it from reaching the cell surface to carry out its signaling functions. The resulting loss of GPR56 function disrupts neuronal migration, leading to intellectual disability, developmental delays, and seizures in individuals with BFPP.
GPR56’s Involvement in Cancer
GPR56 has a complex and varied role in different types of cancer, sometimes suppressing tumor growth and other times promoting it. Its expression levels and specific functions can differ depending on the cancer type and stage. Researchers are investigating GPR56 as a potential target for new cancer therapies due to its diverse involvement in tumor progression.
In glioblastoma (GBM), a highly invasive brain tumor, GPR56 expression is often elevated. GPR56 may inhibit the transition of certain GBM subtypes to a more aggressive mesenchymal phenotype. GPR56’s ability to influence cell adhesion, migration, proliferation, and radioresistance in cancer cells makes it a subject of study in GBM.
In contrast, GPR56 can act as a metastasis suppressor in melanoma, a type of skin cancer. Studies have shown that GPR56 is often downregulated in highly metastatic melanoma cells compared to less aggressive ones. Overexpression of GPR56 in melanoma cells has been observed to suppress tumor growth and metastasis, while reduced GPR56 levels can enhance tumor progression. This suppressive effect may involve GPR56 binding to tissue transglutaminase 2 (TG2), leading to TG2 degradation and reduced deposition of fibronectin, which promotes tumor growth.
GPR56 is also being explored as a therapeutic target in other cancers, such as colorectal cancer (CRC). In CRC, GPR56 expression is often upregulated and can correlate with poorer patient survival. It has been shown to promote tumor growth and drug resistance in CRC cells by increasing the expression of multidrug resistance proteins. The development of GPR56-targeted antibody-drug conjugates (ADCs) is underway, aiming to selectively deliver potent cytotoxic drugs to GPR56-high cancer cells, offering a promising strategy to overcome treatment resistance.