Interdisciplinary Training

Elizabeth Larimore

"Functional analyses of the Fbw7 tumor suppressor: genetic and structural approaches"

Fbw7 is the substrate-recognition component of an SCF ubiquitin ligase that degrades a number of oncoprotein substrates including cyclin E, Myc, Notch, and Jun. Accordingly, Fbw7 is a tumor suppressor and is mutated in many human cancers. Its loss leads to chromosomal instability and tumorigenesis. Fbw7 binds its substrates after they become phosphorylated within a consensus degron sequence called a CPD. CPD phosphorylation creates a high-affinity binding site for Fbw7, which sets into motion the process of substrate ubiquitinylation and degradation. Although phosphorylation of high-affinity CPDs regulates the turnover of several Fbw7 substrates, our recent data suggest this model is incomplete. Other substrates contain low-affinity CPDs that, alone, are insufficient to mediate Fbw7 interaction. However, it appears these 'weak' CPDs are able to cooperatively lead to Fbw7 recruitment and subsequent substrate degradation, a function that requires Fbw7 dimerization. Our data have led to the novel hypothesis that, in addition to canonical interactions with high-affinity CPDs, an Fbw7 dimer can also simultaneously bind two low-affinity CPDs. We propose integrating biochemical and genetic approaches with structure-based studies to gain mechanistic insight into substrate regulation by Fbw7. Given the known importance of Fbw7 and its substrates in tumor-progression pathways, the results of this study will further our understanding of human tumor suppression.

Fred Hutchinson Cancer Research Center is a world leader in research to prevent, detect and treat cancer and other life-threatening diseases.