Ultimately, our findings offer the following: (a) identification of a novel cancer-associated DTX3 isoform (DTX3c) by disclosing a new biological/pathological context for the DTX3-E3-ligase and (b) demonstration of the involvement of UBA1, UBE2N, and Cdc48/p97 as part of the identified complex conditionally docking to the EphB4 C-terminal Degron/PDZ-binding region upon inhibition of the IGF-II-IRA autocrine cancer loop. Here, IGF2 is linked to cancer.