Βeta-catenin N-terminal domain: An enigmatic region prone to cancer causing mutations

The Wnt/β-catenin is a highly conserved signaling pathway involved in cell fate decisions during various stages of development. Dysregulation of canonical Wnt/β-catenin signaling has been associated with various diseases including cancer. β-Catenin, the central component of canonical Wnt signaling pathway, is a multi-functional protein playing both structural and signaling roles. β-Catenin is composed of three distinct domains: N-terminal domain, C-terminal domain and a central armadillo repeat domain. N-terminal domain of β-catenin harbours almost all of the cancer causing mutations, thus deciphering its critical structural and functional roles offers great potential in cancer detection and therapy. Here, in this review, we have collected information from pharmacological analysis, bio-physical and structural studies, molecular modeling, in-vivo and in-vitro assays, and transgenic animal experiments employing various N-terminal domain variants of β-catenin to discuss the interaction of β-catenin with its binding partners that specifically interact with this domain and the implications of these interactions on signaling, cell fate determination, and in tumorigenesis. A thorough understanding of interactions between β-catenin and its binding partners will enable us to more effectively understand how β-catenin switches between its multiple roles, and will lead to the development of specific assays for the identification of small molecules as chemotherapeutic agents to treat diseases, including cancer and neurological disorders, where Wnt/β-catenin signaling is dysregulated.