Since mutations in the human EFNB2-EPHB4 cassette are linked to both vascular and lymphatic diseases, and Rasa1 probably interacts with Ephb4 to inactivate Ras in endothelial cells to regulate vascular development,38,69 we wondered if Ephb4 and its ligand Efnb2 could inhibit Erk signaling to promote lymphatic valve specification upstream of Rasa1. This evidence concerns the gene MAPK1 and lymphatic system disorder.