The canonical Wnt/beta-catenin signaling pathway plays critical roles in both embryonic development and tumorigenesis. Central to the pathway is the turnover of beta-catenin, a protein that functions in both cell adhesion and transcription. In the absence of a Wnt signal, free cytosolic beta-catenin is phopshorylated by a large protein complex called the """"""""beta-catenin destruction complex"""""""" that labels beta-catenin for degradation by an ubiquitin ligase/proteasome system. In the presence of a Wnt signal, the binding of Wnt to its receptor Frizzled and co-receptor LRP leads to the inhibition of beta-catenin phosphorylation in the beta-catenin destruction complex through an unknown mechanism. Inhibition of the beta-catenin destruction complex leads to the accumulation of nuclear beta-catenin, which in turn forms a complex with Tcf and BCL9. The beta-catenin/Tcf/BCL9 complex is essential for the transcriptional activation of Wnt target genes. Constitutive transcription of Wnt target genes is tightly associated with multiple cancer forms. Any compound that disrupts this transcriptional complex can block Wnt responsive transcription and may thus be useful for cancer treatment. ? ? We have three major goals in this proposal. The first is to understand how beta-catenin interacts with both Tcf and BCL9, and how the phosphorylation of beta-catenin Y142 regulates its interaction with BCL9. The second is to provide a structural basis for understanding how beta-catenin switches between cell adhesion and transcription through its interaction with the BCL9-2 protein, and through intramolecular interactions within beta-catenin protein. Proper switching between the cell adhesion and transcription functions of beta-catenin is crucial for normal development, while improper switching can lead to tumorigenesis and metastasis. The third goal is to dissect the structure of the beta-catenin destruction complex, the central regulatory complex in the Wnt/beta-catenin pathway. Our study will be important not only for understanding the mechanism of Wnt signaling, but also for designing Wnt pathway inhibitors. ? ? ?
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