ADGRA2
Domain
The leucine-rich repeats (LRRs) are important for potentiation of Wnt7 signaling.
The RGD motif is involved in integrin ITGAV:ITGB3 binding.
Function
Endothelial receptor which functions together with RECK to enable brain endothelial cells to selectively respond to Wnt7 signals (WNT7A or WNT7B) (PubMed:28289266, PubMed:30026314). Plays a key role in Wnt7-specific responses, such as endothelial cell sprouting and migration in the forebrain and neural tube, and establishment of the blood-brain barrier (By similarity). Acts as a Wnt7-specific coactivator of canonical Wnt signaling: required to deliver RECK-bound Wnt7 to frizzled by assembling a higher-order RECK-ADGRA2-Fzd-LRP5-LRP6 complex (PubMed:30026314). ADGRA2-tethering function does not rely on its G-protein coupled receptor (GPCR) structure but instead on its combined capacity to interact with RECK extracellularly and recruit the Dishevelled scaffolding protein intracellularly (PubMed:30026314). Binds to the glycosaminoglycans heparin, heparin sulfate, chondroitin sulfate and dermatan sulfate (PubMed:16982628).
Post-translational modifications
Glycosylated.
Proteolytically cleaved into two subunits, an extracellular subunit and a seven-transmembrane subunit (PubMed:16982628, PubMed:22013897). Cleaved by thrombin (F2) and MMP1 (PubMed:22013897). Also cleaved by MMP9, with lower efficiency (PubMed:16982628, PubMed:22013897). Presence of the protein disulfide-isomerase P4HB at the cell surface is additionally required for shedding of the extracellular subunit, suggesting that the subunits are linked by disulfide bonds (PubMed:22013897). Shedding is enhanced by the growth factor FGF2 and may promote cell survival during angiogenesis (PubMed:16982628).
Sequence Similarities
Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.
Tissue Specificity
Expressed in endothelial cells (at protein level) (PubMed:15021905, PubMed:16982628). Abundantly expressed in heart, placenta, ovary, small intestine, and colon (PubMed:15021905).
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Cell projection
- Filopodium
- Enriched at lateral cell borders and also at sites of cell-ECM (extracellular matrix) contact.
Alternative names
GPR124, KIAA1531, TEM5, ADGRA2, Adhesion G protein-coupled receptor A2, G-protein coupled receptor 124, Tumor endothelial marker 5