Ubiquitin-mediated proteolysis is one of the major mechanisms used by the cell to regulate the protein composition of signaling networks. E6AP, which was originally identified in the Howley lab as a human papillomavirus (HPV) 16 E6 binding protein, functions as a ubiquitin- protein ligase (E3) in p53 degradation. In the absence of HPV16 E6, E6AP is known to function as an E3 enzyme, however, its substrates remain unclear. Recent work from the Howley lab has identified several potential substrates for E6AP, including Blk, a member of the Src family of non-receptor tyrosine kinases. Studies of the effects of E6AP on BLK have demonstrated that E6AP selectively targets the kinase active form of Blk for degradation. The goal of this proposal is to determine if E6AP affects the stability of c-Src and V-Src. Preliminary data indicates that E6AP interacts with c-Src is in fact a substrate for E6AP and if the activated forms of this kinase are selectively degraded. In addition, the effects of E6AP on v-Src will be studied to determine if v- are selectively degraded. In addition, the effects of E6AP on v-SRC will be studied to determine if v-SRC is unstable or is able to escape targeted degradation. The effects of HPV16 E6 on E6AP mediated degradation of c-Src will also be analyzed, as HPV16 E6 may alter he substrate specificity of E6AP, degradation of c-Src will also be analyzed, as HPV16 E6 may alter the substrate specificity of E6AP. Together, these studies will further our understanding of human cancer by providing insight into cellular transformation both by non-receptor tyrosine kinases and by human papillomaviruses.
| Aizer, Ayal A; Urun, Yuksel; McKay, Rana R et al. (2014) Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC). BJU Int 113:E67-74 |
