Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 it is involved in the regulation of cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessel remodeling and permeability. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells. ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein] Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses (By similarity). Interacts with RASA1; the interaction depends on EPHB4 tyrosine-phosphorylation (By similarity). Expressed in various organ systems, including lung, liver, kidney, intestine, muscle and heart (PubMed:7478528). Expressed in myogenic progenitor cells (PubMed:27446912). Specifically expressed in the developing cardiovascular system with higher expression in veins. First detected in the developing anterior cardinal vein at 8.75 dpc. Abundant expression at 16.5 dpc in various organ systems, including thymus, heart, lung and kidney, where it is associated with cells of endothelial origin. In myogenic progenitor cells, highly expressed during early development (11.5 dpc) and progressively repressed as developments proceeds (PubMed:27446912). Phosphorylated; autophosphorylation is stimulated by EFNB2. Embryo display cardiovascular defects and lethality with very high penetrance. Growth retardation is observed at 9.5 dpc with arrested heart development and lack of blood flow. By 10.5 dpc degeneration and necrosis are apparent throughout the embryo. Conditional lymphovenous valves knockouts show a complete loss of lymphatic valves (PubMed:27400125). Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.