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Proteins in the cell are subject to diverse covalent modifications that serve to alter their activity, localization, or turnover. Such modifications include ubiquitination and covalent attachment of ubiquitin-like molecules (e.g., SUMO or small ubiquitin-like modifier). We initially became interested in how these modifications regulate cell cycle proteins that could disrupt TGF-β signaling(Liu et al., 2000). We subsequently found further interplay between TGF-β signaling and protein degradation mechanisms (Wang et al., 2004, MacDonald et al., 2004). More recently, we have sought to determine the biochemical mechanisms by which E3 ligases mediate ubiquitination of their substrates (Wang et al., 2004, Ungermannova et al., 2005, Wang et al., 2005; Wang et al. 2006). We continue to pursue these studies using structural and biochemical techniques.  We are mainly interested in two SCF type of ubiquitin ligases (SCFSkp2 and SCFFbx4; Zeng et al. 2010).  More recently we developed high throughput screening assays for identifying small molecule inhibitors of SCF E3 ligase in an effort to curb excessive proteolysis of p27Kip1 which is a tumor suppressor protein perturbed in a variety of human tumors (Ungermannova et al. 2012 and 2013). A peptide inhibitor of SCFFbx4 was developed in collaboration with Professor Yin in our department (Lee et al. 2013). In addition, studies were done to establish the functional importance of post-translational modifications on the activity of transcription factors. Here, muscle differentiation, which is largely driven through transcriptional regulation, was used as a model system (Riquelme et al., 2006, 2 separate publications).