Distinct Wnt/β-catenin signaling cascades operate within endothelial cells (ECs) to control central nervous system vascular invasion and blood-brain barrier formation. In the mouse forebrain and zebrafish brain, Wnt7 ligands prime perineural ECs for invasion. In order to recognize these ligands, and hence to be competent for brain invasion, endothelial cells assemble unique receptor complexes at the plasma membrane that, in addition to classical receptor components like Fzd/Lrp, contain Adgra2 (previously known as Gpr124), an orphan member of the adhesion class of G protein-coupled receptors and Reck, a GPI-anchored glycoprotein. Adgra2 and Reck physically interact to assemble a potent synergistic Wnt7-specific co-activator complex that controls tip cell function during brain vascularization. How the partners interact and whether Adgra2 transmits a signal inside the receiving EC remains to be determined. In light of their function as key brain angiogenic regulators, determining the molecular modalities of Adgra2/Reck activity is of both clinical and fundamental importance. Adhesion class G protein-coupled receptors (aGPCRs) form the second largest class of GPCRs that context-dependently function as adhesion molecules, signal transducing GPCRs, or both concurrently. Adgra2 is a typical aGPCR characterized by a long extracellular domain containing multiple protein adhesion motifs, followed by a membrane-proximal GPCR-autoproteolysis autoinduced (GAIN) domain, seven membrane-spanning domains and a C-terminal intracellular domain. Through a combination of mutagenesis and in vivo brain angiogenic assays, we have molecularly dissected the Adgra2 protein motifs and determined their contribution to protein trafficking, interaction with Reck and angiogenic function. These analyses reveal key determinants of Adgra2/Reck function, uncover a novel mode of action for adhesion GPCRs and provide insights into the pharmacological potential of the Adgra2/Reck complex in cerebrovascular disorders.