Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins are small signaling molecules that are involved in many aspects of cell function. It has been assumed that Ub and Ubl have functionally distinct roles because they use different conjugation machineries and bind to different effector proteins. This paradigm, however, must be revisited after recent findings that signaling cascades mediated by Ub and the Ubl NEDD8 (Neural precursor cell–Expressed Developmentally Down-regulated 8) in the regulation of epidermal growth factor receptor (EGFR) endocytosis are redundant. In this context, Ub and NEDD8 share the same E3 ligase, Cbl, and are recognized by identical components of the endocytic sorting machinery. This unexpected redundancy introduces additional complexity to the current view of Ub signaling pathways.
