Alternative titles; symbols
HGNC Approved Gene Symbol: ADGRL4
Cytogenetic location: 1p31.1 Genomic coordinates (GRCh38): 1:78,889,764-79,006,730 (from NCBI)
ADGRL4 is a G protein-coupled receptor expressed on the surface of endothelial cells and vascular smooth muscle cells that plays a role in angiogenesis (Masiero et al., 2013).
Nechiporuk et al. (2001) cloned rat Adgrl4, which they called Etl. The deduced 738-amino acid protein has an N-terminal signal sequence, followed by a large extracellular domain, a 7-transmembrane region, and a short cytoplasmic tail. The extracellular domain has a short lectin (see 606782)-type region, an EGF (131530)-like domain, 2 identical Ca(2+)-binding EGF domains, a ser/thr linker, and a juxtamembrane cys-rich proteolysis domain. It also has potential sites for hydroxylation, O-glycosylation, N-glycosylation, and phosphorylation. Northern blot analysis detected a 4.4-kb Etl transcript in all 8 rat tissues examined except testis. Expression was also detected in adult human heart, but not fetal heart. Expression in rat heart increased significantly after birth. In situ hybridization of 12-day-old rat heart and lung detected Etl in cardiomyocytes and in vascular smooth muscle cells of coronary vessels in the epicardial layer. In lung, Etl was expressed in vascular and bronchiolar smooth muscles. Confocal microscopy localized epitope-tagged rat Etl near the plasma membrane and in intracellular vesicles. Western blot analysis and differential solubilization revealed that rat Etl was cleaved within the extracellular domain. The cleaved product formed dimers and maintained close association with the plasma membrane.
Masiero et al. (2013) reported that full-length human ADGRL4, which they called ELTD1, has an N-terminal EGF-like domain, followed by a single Ca(2+)-binding EGF-like domain, a domain of unknown function (DUF3497), a proteolysis domain, 7 transmembrane domains, and a short C-terminal cytoplasmic tail. ELTD1 has a calculated molecular mass of 78 kD. Epitope-tagged ELTD1 was expressed on the cell surface of transfected HEK293T cells. Immunohistochemical analysis of normal and tumor tissues detected ELTD1 in vascular smooth muscle cells, with weaker expression in endothelial cells of arteries and arterioles. Western blot analysis of human umbilical vein endothelial cells (HUVECs) and ELTD1-transfected HEK293T cells showed multiple bands ranging from 95 to 70 kD. Endoglycosidase treatment shifted the mass of ELTD1 to approximately 44 kD, possibly representing the proteolytically released extracellular domain. Analysis of cell lysates under nondenaturing conditions suggested that ELTD1 formed monomers, dimers, trimers, and tetramers.
Nechiporuk et al. (2001) determined that the ADGRL4 gene contains at least 13 exons.
By radiation hybrid and database analysis, Nechiporuk et al. (2001) mapped the ADGRL4 gene to chromosome 1p33-p32. They mapped the mouse Adgrl4 gene to a region of chromosome 3H3-H4 that shares homology of synteny with human chromosome 1p33-p32.
Hartz (2015) mapped the ADGRL4 gene to chromosome 1p31.1 based on an alignment of the ADGRL4 sequence (GenBank AF192403) with the genomic sequence (GRCh38).
Using HUVECs, Masiero et al. (2013) found that expression of ELTD1 was induced in an additive fashion by VEGF (VEGFA; 192240) and basic FGF (FGF1; 131220). ELTD1 was downregulated by DLL4 (605185). Expression of ELTD1 was significantly increased in several tumor tissues compared with normal tissues. Higher ELTD1 expression was associated with less-aggressive cancer features and better prognosis in all tumor types analyzed. Knockdown of ELTD1 in HUVECs via small interfering RNA reduced adherence and sprouting in a 3-dimensional angiogenesis assay. Knockdown of ELTD1 in umbilical vein smooth muscle cells reduced cell adhesion and viability. Knockdown of Eltd1 also reduced tumor growth in mouse models.
Masiero et al. (2013) noted that Eltd1 is the only member of its receptor family conserved in zebrafish. They found that morpholino-mediated knockdown of eltd1 in zebrafish resulted in severe vascular defects and confirmed that knockdown of dll4 in zebrafish caused arterial hyperbranching. Coinjecting morpholinos against eltd1 and dll4 partly rescued the vascular defects in eltd1-knockdown embryos and the arterial hyperbranching in dll4-knockdown embryos.
Hartz, P. A. Personal Communication. Baltimore, Md. 6/12/2015.
Masiero, M., Simoes, F. C., Han, H. D., Snell, C., Peterkin, T., Bridges, E., Mangala, L. S., Wu, S. Y.-Y., Pradeep, S., Li, D., Han, C., Dalton, H., and 9 others. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell 24: 229-241, 2013. [PubMed: 23871637] [Full Text: https://doi.org/10.1016/j.ccr.2013.06.004]
Nechiporuk, T., Urness, L. D., Keating, M. T. ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart: ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily. J. Biol. Chem. 276: 4150-4157, 2001. [PubMed: 11050079] [Full Text: https://doi.org/10.1074/jbc.M004814200]