# ADGRG4

## Overview
ADGRG4, or adhesion G protein-coupled receptor G4, is a gene that encodes a member of the adhesion GPCR family, which is characterized by a seven-transmembrane (7TM) domain structure. The protein product of ADGRG4, adhesion G protein-coupled receptor G4, is involved in various cellular processes, including cell adhesion, signaling, and interaction with the extracellular matrix. This receptor features a large extracellular domain (ECD) with a GPCR autoproteolysis-inducing (GAIN) domain, facilitating its cleavage into an N-terminal fragment (NTF) and a C-terminal fragment (CTF) that remain associated at the cell surface (Knapp2016Adhesion; Arimont2019Identification). The receptor's intracellular domain (ICD) is crucial for downstream signaling pathways, and its structure shares similarities with class B secretin receptors, which are important for G protein coupling (Peeters2016Getting). ADGRG4 is expressed in various tissues, including the gastrointestinal tract, and is implicated in neuroendocrine functions, although its precise physiological roles and potential involvement in disease mechanisms require further exploration (Peeters2016Getting).

## Structure
ADGRG4, also known as adhesion G protein-coupled receptor G4, is a member of the adhesion GPCR family characterized by a seven-transmembrane (7TM) domain structure. This receptor features a large extracellular domain (ECD) that includes a GPCR autoproteolysis-inducing (GAIN) domain, which facilitates autoproteolytic cleavage into an N-terminal fragment (NTF) and a C-terminal fragment (CTF) that remain associated at the cell surface (Knapp2016Adhesion; Arimont2019Identification). The ECD also contains a pentraxin (PTX) domain and an RGD motif, which are involved in cell adhesion processes (Krishnan2016Classification).

The intracellular domain (ICD) of ADGRG4 includes the 7TM domain, which is crucial for signaling pathways. The receptor's structure is similar to class B secretin receptors, with conserved motifs that are important for receptor function and G protein coupling (Krishnan2016Classification; Peeters2016Getting). Post-translational modifications such as glycosylation and phosphorylation are likely involved in its function, although specific details are not provided in the context.

Mutational analysis has identified key motifs within the transmembrane domains that are essential for receptor activity, including the DRY motif in TM3 and the CWxP motif in TM6 (Peeters2016Getting). These structural features highlight the complex nature of ADGRG4 and its role in cellular signaling and adhesion.

## Function
ADGRG4, or adhesion G protein-coupled receptor G4, is a member of the adhesion GPCR family, which plays a significant role in cellular processes such as cell-cell recognition, differentiation, migration, and adhesion (Peeters2016Getting). The receptor is characterized by a large extracellular domain (ECD) that facilitates interactions with other cells or the extracellular matrix, and an intracellular domain (ICD) that is involved in downstream signaling pathways (Knapp2016Adhesion). 

ADGRG4 is known for its constitutive activity, particularly in its truncated form, which can activate signaling pathways even in the absence of a ligand. This activity has been demonstrated in both mammalian and yeast cells, suggesting its involvement in fundamental cellular processes (Peeters2016Getting). The receptor's 7-transmembrane (7TM) domain is crucial for its function, and specific sequence motifs within this domain are essential for receptor activity (Peeters2016Getting).

The molecular processes involving ADGRG4 include its potential role in neuroendocrine functions, as it is expressed in various tissues, including the gastrointestinal tract. However, the exact physiological roles of ADGRG4 in healthy human cells require further investigation (Peeters2016Getting).

## Clinical Significance
ADGRG4, also known as adhesion G protein-coupled receptor G4, has been implicated in various diseases, particularly in the context of cancer. In solid tumors, ADGRG4 is frequently mutated, with notable occurrences in melanoma (SKCM). These mutations may indicate DNA damage accumulation and could serve as tumor markers, although their role as drivers of tumor progression remains uncertain due to the lack of enrichment in specific mutation sites and statistically significant mutation rates above the background (Sriram2019GPCRs).

In the realm of kidney diseases, ADGRG4 is associated with chronic kidney disease (CKD), showing a significant fold change in expression. However, specific mutations or expression alterations beyond this association are not detailed (CazorlaVázquez2018Adhesion).

The gene is also noted for its overexpression in pancreatic ductal adenocarcinoma (PDAC), where it is one of the most highly differentially expressed GPCRs. This overexpression is correlated with cancer-related pathways, suggesting a potential role in tumorigenic processes (Sriram2019GPCRs).

Overall, while ADGRG4 is linked to several conditions, its precise role in disease mechanisms and potential as a therapeutic target requires further investigation.


## References


[1. (Arimont2019Identification) Marta Arimont, Melanie van der Woude, Rob Leurs, Henry F. Vischer, Chris de Graaf, and Saskia Nijmeijer. Identification of key structural motifs involved in 7 transmembrane signaling of adhesion gpcrs. ACS Pharmacology & Translational Science, 2(2):101–113, January 2019. URL: http://dx.doi.org/10.1021/acsptsci.8b00051, doi:10.1021/acsptsci.8b00051. This article has 10 citations.](https://doi.org/10.1021/acsptsci.8b00051)

2. (Sriram2019GPCRs) GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors. This article has 11 citations.

[3. (Krishnan2016Classification) Arunkumar Krishnan, Saskia Nijmeijer, Chris de Graaf, and Helgi B. Schiöth. Classification, Nomenclature, and Structural Aspects of Adhesion GPCRs, pages 15–41. Springer International Publishing, 2016. URL: http://dx.doi.org/10.1007/978-3-319-41523-9_2, doi:10.1007/978-3-319-41523-9_2. This article has 31 citations.](https://doi.org/10.1007/978-3-319-41523-9_2)

[4. (Knapp2016Adhesion) Barbara Knapp and Uwe Wolfrum. Adhesion GPCR-Related Protein Networks, pages 147–178. Springer International Publishing, 2016. URL: http://dx.doi.org/10.1007/978-3-319-41523-9_8, doi:10.1007/978-3-319-41523-9_8. This article has 19 citations.](https://doi.org/10.1007/978-3-319-41523-9_8)

[5. (CazorlaVázquez2018Adhesion) Salvador Cazorla-Vázquez and Felix B. Engel. Adhesion gpcrs in kidney development and disease. Frontiers in Cell and Developmental Biology, February 2018. URL: http://dx.doi.org/10.3389/fcell.2018.00009, doi:10.3389/fcell.2018.00009. This article has 23 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2018.00009)

[6. (Peeters2016Getting) Miriam C. Peeters, Iris Mos, Eelke B. Lenselink, Martina Lucchesi, Adriaan P. IJzerman, and Thue W. Schwartz. Getting from a to b—exploring the activation motifs of the class b adhesion g protein‐coupled receptor subfamily g member 4/gpr112. The FASEB Journal, 30(5):1836–1848, January 2016. URL: http://dx.doi.org/10.1096/fj.201500110, doi:10.1096/fj.201500110. This article has 17 citations.](https://doi.org/10.1096/fj.201500110)