The present study clearly establishes EphB4 as a controlled downstream target for the autocrine IGF-II loop which, per se, is a hallmark for the majority of human and mammalian solid cancers [16, 18, 20, 26] and demonstrate that EphB4 protein expression in mesothelioma cell lines is strictly dependent upon a steady-state interplay between IGF-II induced tyrosine phosphorylation and the ubiquitination of its C-terminal region acting as a molecular switch for EphB4 protein stabilization versus degradation. Here, EPHB4 is linked to mesothelioma.