Adgrg1, also known as GPR56, is an adhesion G protein-coupled receptor. It has diverse physiological functions in the central and peripheral nervous systems, reproductive system, muscle hypertrophy, immune regulation, and hematopoietic stem cell generation. It may be involved in multiple signaling pathways, and its abnormal expression is associated with various pathological processes [2]. Genetic models are valuable for studying its function.

In tumor-related studies, ADGRG1/GPR56 has both tumor-suppressive and tumor-promoting functions, and is recognized as a potential biomarker/prognostic factor for specific cancer types [1]. In acute myeloid leukemia, ADGRG1 can serve as a specific marker for tumor-reactive T cells, which may be harnessed for adoptive cell therapy [4]. In cervical squamous carcinoma, knockdown of ADGRG1 suppresses cell proliferation, migration, and invasion, and increases cell sensitivity to cisplatin, suggesting it acts as an oncogene [9]. In cytotoxic lymphocytes, it regulates cell migration and effector functions and acts as an inhibitory immune checkpoint [3]. In melanoma cells, it plays a role in cancer cell adhesion, migration and metastasis [6]. In bilateral frontoparietal polymicrogyria, loss-of-function of the ADGRG1 gene is attributed to the disease, and a novel missense variant (p.Leu290Pro) was found to reduce cell surface GPR56 expression [7]. In the placenta, Adgrg1 is a new transcriptional target of Hand1, affecting cell migration and invasion during trophoblast giant cell differentiation [5]. Also, GPR56 renders cells resistant to ferroptosis, and 17α-hydroxypregnenolone acts as its agonist to antagonize ferroptosis and attenuate liver injury [8]. ADGRG1 also forms 7-transmembrane-driven homo-oligomers on the plasma membrane, and Stachel motif interactions may influence the conformation of these receptor complexes [10].

In conclusion, Adgrg1 is a versatile adhesion G protein-coupled receptor with important functions in multiple physiological and pathological processes. Gene knockout or conditional knockout mouse models could potentially further clarify its role in diseases such as tumors, bilateral frontoparietal polymicrogyria, and placental-associated diseases, contributing to a better understanding of disease mechanisms and potential therapeutic targets.

References:

1. Ng, Kwai-Fong, Chen, Tse-Ching, Stacey, Martin, Lin, Hsi-Hsien. 2021. Role of ADGRG1/GPR56 in Tumor Progression. In Cells, 10, . doi:10.3390/cells10123352. https://pubmed.ncbi.nlm.nih.gov/34943858/

2. Singh, Abhishek Kumar, Lin, Hsi-Hsien. 2021. The role of GPR56/ADGRG1 in health and disease. In Biomedical journal, 44, 534-547. doi:10.1016/j.bj.2021.04.012. https://pubmed.ncbi.nlm.nih.gov/34654683/

3. Hsiao, Cheng-Chih, Vos, Els, van Gisbergen, Klaas P J M, Hamann, Jörg. 2023. The adhesion G protein-coupled receptor GPR56/ADGRG1 in cytotoxic lymphocytes. In Basic & clinical pharmacology & toxicology, 133, 286-294. doi:10.1111/bcpt.13841. https://pubmed.ncbi.nlm.nih.gov/36750420/

4. Mei, Yihan, Liu, Yu, Liu, Wenbing, Qiu, Shaowei, Wang, Jianxiang. 2024. Identifying ADGRG1 as a specific marker for tumor-reactive T cells in acute myeloid leukemia. In Experimental hematology & oncology, 13, 92. doi:10.1186/s40164-024-00560-0. https://pubmed.ncbi.nlm.nih.gov/39243082/

5. Yu, Yongqin, Mu, Change, Xu, Yingchun, Wang, Haibin, Lu, Jinhua. 2022. Adgrg1 is a new transcriptional target of Hand1 during trophoblast giant cell differentiation. In Journal of reproductive immunology, 154, 103753. doi:10.1016/j.jri.2022.103753. https://pubmed.ncbi.nlm.nih.gov/36228547/

6. Huang, Kuan-Yeh, Lin, Hsi-Hsien. 2018. The Activation and Signaling Mechanisms of GPR56/ADGRG1 in Melanoma Cell. In Frontiers in oncology, 8, 304. doi:10.3389/fonc.2018.00304. https://pubmed.ncbi.nlm.nih.gov/30135857/

7. Kuo, Cheng-Yen, Tsai, Meng-Han, Lin, Hsi-Hsien, Hung, Po-Cheng, Lin, Kuang-Lin. 2023. Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral Frontoparietal Polymicrogyria: The electroclinical change from infancy to adulthood after Callosotomy in three siblings. In Epilepsia open, 8, 154-164. doi:10.1002/epi4.12685. https://pubmed.ncbi.nlm.nih.gov/36524291/

8. Lin, Hui, Ma, Chuanshun, Zhuang, Xiao, Sun, Jin-Peng, Chu, Bo. 2024. Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury. In Cell metabolism, 36, 2402-2418.e10. doi:10.1016/j.cmet.2024.09.007. https://pubmed.ncbi.nlm.nih.gov/39389061/

9. Zhang, Shuo, Guo, Kui, Liang, Ying, Liu, Shuyan, Yang, Xingsheng. 2021. ADGRG1 Is a Predictor of Chemoresistance and Poor Survival in Cervical Squamous Carcinoma. In Frontiers in oncology, 11, 671895. doi:10.3389/fonc.2021.671895. https://pubmed.ncbi.nlm.nih.gov/34367958/

10. Cevheroğlu, Orkun, Demirbaş, Berkay, Öğütcü, Dilara, Murat, Merve. 2024. ADGRG1, an adhesion G protein-coupled receptor, forms oligomers. In The FEBS journal, 291, 2461-2478. doi:10.1111/febs.17117. https://pubmed.ncbi.nlm.nih.gov/38468592/