Similar to ubiquitin, Nedd8 signals to target proteins through an enzymatic cascade composed of Nedd8-specific E1 (activating)- and E2 (conjugating)-enzymes (1,2). The E2 ligase specific for Nedd8 is Ubc12 (3-5). Ubc12 forms a heterodimeric conjugate with NEDD8 in order to catalyze the transfer of NEDD8 from E1 to lysine side chains of target proteins (1,2). Well known targets of NEDD8 belong to the cullin family of E3 ligases. Neddylation of cullin activates the related ubiquitin E3 complex by promoting its interaction with ubiquitin-E2 ligase and catalyzing downstream target protein ubiquitination (6-7). Neddylation of the cullins on SCFROC1, SCFbTrCP, and SCFSKP2 has been shown to be required for controlling important signaling targets such as IkB, NF-kB, and p27 Kip (8-10), thereby regulating cell cycle progression, signaling cascades, and developmental programming processes (11).