EPHB4 (EPH receptor B4) is a receptor tyrosine kinase that binds ephrin-B ligands on adjacent cells to mediate bidirectional signaling involved in vascular development and cell-cell interactions. EPHB4 functions through forward signaling that controls cellular repulsion and segregation, while also participating in reverse signaling pathways 1. The receptor plays a central role in angiogenesis and lymphangiogenesis by regulating endothelial cell sprouting and motility, partly through coupling VEGFR3 internalization to Rac1/Akt/ERK signaling 1. Critically, EPHB4 interacts with RASA1 (p120 RasGAP) to suppress Ras-MAPK pathway activation; this interaction is essential for lymphatic valve specification and maintenance by dampening PIEZO1-induced Ras signaling in response to oscillatory shear stress 2. Germline loss-of-function EPHB4 mutations cause capillary malformation-arteriovenous malformation 2 (CM-AVM2), a multifocal vascular disorder phenotypically similar to RASA1-related CM-AVM1 3. EPHB4 mutations are also enriched in vein of Galen malformations, the most severe congenital brain arteriovenous malformations, particularly when combined with additional "second-hit" variants affecting cerebrovascular development 4. Beyond vascular disease, aberrant EFNB1-EPHB4 interactions driven by TP53 mutations promote epithelial-mesenchymal transition and proliferation in esophageal squamous-cell carcinoma through SRC/ERK/AKT signaling 5. EPHB4 signaling also influences neurooncological disease progression and antiangiogenic therapy resistance 6.