During cellular homeostasis, many oncoproteins (e.g. Myc and Notch) are degraded by SCF(Fbw7), a modular E3 ubiquitin ligase that contains Fbw7 as the substrate adapter. Degradation is antagonized by Usp28, a deubiquitylating enzyme that reverses Fbw7-mediated substrate ubiquitylation. Ablation of Usp28 in the intestine downregulates Fbw7 substrates, attenuates stem cell proliferation and delays tumorigenesis. Usp28 can also antagonize autocatalytic ubiquitylation of Fbw7 and thereby stabilize it. Loss of Usp28 in several tissues, including the liver and pancreas, induces downregulation of Fbw7 and accumulation of Fbw7 substrates. Collectively, these data demonstrate a strong functional and physical relationship between Fbw7 and Usp28. However, molecular determinants of Fbw7-Usp28 interaction, the involvement of additional proteins and underlying regulatory mechanisms still remain elusive. Project B1 therefore aims to elucidate the composition of the Fbw7-Usp28 complex and the structural basis for its assembly.