The ultimate demonstration of the potential of the autocrine IGF-II/IRA axis in cancer came from the recent finding that, when activated by IGF-II, the IRA variant is able to acutely and reversibly activate a post-translational, ubiquitin-dependent, and IGF1R-independent degradation rescue signal, causing EphB4 ectopic expression in malignant mesothelioma cell lines [14]. Here, EPHB4 is linked to cancer.