Introduction of ADGRL4

Adhesion G protein-coupled receptor L4 (ADGRL4), also known as ETL, ELTD1 or KPG_003, is encoded by the ELTD1 gene. Based on its sequence, ADGRL4 is a member of the secretin family of G protein-coupled peptide hormone receptors and belongs to the epidermal growth factor 7-transmembrane (EGF-TM7) subfamily. ADGRL4 plays a role in angiogenesis, both physiological and pathological, as well as glioblastoma and the protein levels of ADGRL4 are significantly higher in humans and rodent gliomas. Structurally, it contains a large extracellular domain with EGF-like repeats, a seven transmembrane domain, and a short cytoplasmic tail.

Function of ADGRL4 Membrane Protein

ADGRL4 is discovered to be developmentally regulated in rat fetal and postnatal cardiomyocytes and has also been identified as a ligand dermatan sulfate in rheumatoid synovial tissue in patients with rheumatoid arthritis. More importantly, ADGRL4 has been associated as an endothelial marker in microvasculature. Specificity of the ADGRL4 probe may be in areas associated with neovascularization. Compared with low-grade gliomas, ADGRL4 is significantly higher in high-grade gliomas. This marker can be used to identify high-grade glioma tissues, which is better than traditional immunohistochemical (IHC) markers, traditional immunohistochemistry (IHC)-inducible factor-1α of oxygen-inducible factor 9. ADGRL4 gene expression is associated with tumor grade, survival across grades, and an increase in mesenchymal subtypes.

Fig.1 ELTD1’s putative structure and conservation. (Favara DM, et al. 2014)

Application of ADGRL4 Membrane Protein in Literature

1. Ziegler J., et.al. ELTD1, an effective anti-angiogenic target for gliomas: preclinical assessment in mouse GL261 and human G55 xenograft glioma models. Neuro Oncol. 2017, 19(2): 175-185. PubMed ID: 27416955

Authors in this group discovered a new biomarker for high-grade gliomas, ELTD1 via bioinformatics, and validated that ELTD1 protein levels are significantly higher in human and rodent gliomas. Anti-ELTD1 antibodies could be a valuable new clinical anti-angiogenic therapeutic for high-grade gliomas.

2. Lu S., et.al. Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4). PLoS One. 2017, 12(8): e0183166. PubMed ID: 28806758

This article reveals that the absence of ELTD1 and GPR116 showed malformations of the aortic arch arteries and the cardiac outflow tract leading to approximately 50% of mutant perinatal lethality. This indicates that loss of GPR116 and ELTD1 expressed accounts for the observed cardiovascular and renal defects.

3. Dai S., et.al. MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme. Biochem Biophys Res Commun. 2015, 467(2): 204-10. PubMed ID: 26449464

The article reports that ectopic expression of miR-139-5p in GBM cell lines significantly suppressed cell proliferation and inducing apoptosis. Therefore, miR-139-5p can be used to suppresses glioma cell proliferation via targeting ELTD1 and regulating cell cycle.

4. Masiero M., et.al. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell. 2013, 24(2): 229-41. PubMed ID: 23871637

Authors in this group identified the expression of ELTD1 is induced by VEGF/bFGF and repressed by DLL4 signaling. ELTD1 is believed to play an important role in blood vessel formation.

5. Towner RA., et.al. ELTD1, a potential new biomarker for gliomas. Neurosurgery. 2013, 72(1): 77-90. PubMed ID: 23096411

The study suggests that ELTD1 is a putative glioma-associated biomarker, which may serve as an additional biomarker for preclinical and clinical diagnosis of gliomas.

ADGRL4 Preparation Options

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Reference

1. Favara DM, et al. (2014). A review of ELTD1, a pro-angiogenic adhesion GPCR. Biochem Soc Trans. 42(6), 1658-64.

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