These results reveal for the first time the role of EphA2 in clathrin mediated endocytosis of a virus and c-Cbl directed polyubiquitination of EphA2 regulating KSHV infection by coordinating signal induction and underscores EphA2 and c-Cbl as potential targets to intervene in KSHV entry and infection. This evidence concerns the gene EPHA2 and infection.