In the course of studies conducted to delineate the mechanism underlying EphA2 dependent modulation clearly demonstrated for the first time the following findings: i) EphA2 associates with and influences the tyrosine phosphorylation of clathrin heavy chain; ii) EphA2 plays a role in clathrin mediated endocytosis of a virus; iii) c-Cbl E3 ubiquitin ligase actively participates in KSHV entry by polyubiquitinating EphA2 which is necessary for EphA2 to be effective as an internalization signal for CME of KSHV and trafficking towards the endosome but not lysosome for successful infection. The gene discussed is CLTC; the disease is infection.