Cancer is a multifaceted disease in which dysregulated gene-expression and other aberrant activities are crucial for neoplastic initiation and progression. One of the major mechanisms that regulates gene function is protein ubiquitination. This modification can impose diverse effects on proteins, ranging from proteolysis to modulation of protein structure, localization and function. Central to this evolutionary conserved pathway are the E3 ubiquitin ligases (E3s), which confer specificity to ubiquitination. Many E3s are encoded by tumor suppressors or oncogenes and make pivotal contribution to the pathogenesis of many cancers. Among the different types of E3s, HECT-type E3 ligases have been significantly less explored. Consequently, our knowledge of their substrates, biological functions and mechanisms of regulation in cancer is quite limited.
Our primary research objective is to delineate the spectrum of biological activities of a HECT-type E3 ligase Smurf2. Recently, we identified Smurf2 as a novel tumor suppressor gene (Blank M et al., Nature Medicine 2012). Our continued interest focuses on understanding the role that Smurf2 plays in the regulation of gene expression and cell growth, DNA damage response and repair, chromatin biology (epigenetics) and genomic integrity — intimately connected processes that are frequently compromised in cancer cells. Using a multidisciplinary approach spanning these areas, we are determined to shed light on the multifaceted role that HECT-type E3 ligases in general and Smurf2 in particular, play in cancer biology. We also will gain insight into the regulatory mechanisms governing Smurf2 biodistribution and functional activities.
Another research goal is to investigate the involvement of other HECT type E3 ligases in tumorigenesis, initially focusing on the NEDD4 protein family, members of which have the same domain organization as Smurf2, and potentially share intracellular substrates and pathways. By extensively studying Smurf2 and its homologues, we hope to learn how these molecules participate in normal and aberrant cellular processes. We believe such knowledge will provide novel targets for therapeutic intervention in cancer treatment.