科研之友
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摘要
Recently, we showed that the ubiquitin ligase E6AP stabilizes beta-catenin and activates its transcriptional activity. These activities were enhanced by the human papillomavirus (HPV) E6 protein. In the present study, we explored the function of E6AP, which increases beta-catenin stabilization and transcriptional activation. Here, we report that E6AP interacts with beta-catenin and mediates its nonproteolytic ubiquitylation, as evidenced in transiently transfected cell-based and in vitro reconstitution ubiquitylation assays. Overexpression of E6AP increased beta-catenin polyubiquitylation and, consistent with that, knockdown or knock-out of E6AP expression reduced beta-catenin polyubiquitylation. The ubiquitylation of beta-catenin by E6AP was dependent on its E3 ubiquitin ligase activity, but it was proteasome-independent and did not require HPV-E6, phosphorylation of beta-catenin by glycogen synthase kinase 3 beta (GSK3 beta) or activity of the beta-catenin 'destruction complex'. We also show that transcriptional activation of b-catenin by E6AP is coupled with beta-catenin protein stabilization, but not its ubiquitylation. In contrast to b-catenin ubiquitylation, beta-catenin protein stability and its transcriptional activity were absolutely dependent on the activity of the destruction complex and phosphorylation by GSK3 beta. Collectively, our data uncover a dual role for E6AP in the regulation of beta-catenin ubiquitylation, stability and transcriptional activity, with HPV-E6 enhancing only part of E6AP activities.
- 出版日期2016-12
- 单位河北医科大学
