Abstract 5157: Ubiquitin-dependent regulation of AKT by NEDD4-1

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.5157-5157
• Main Authors: Wang, Xinjiang, Fan, Chuan-Dong, Lum, Michelle A., Xu, Chao, Black, Jennifer D.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-5157

Several E3 ligases have been reported to regulate AKT stability and activation through ubiquitination. We found that NEDD4-1 is a novel E3 ligase involved in ubiquitin-dependent regulation of AKT. NEDD4-1 physically interacts with AKT and mediates AKT ubiquitination in vitro and in vivo. NEDD4-1 catalyzes K63-type polyubiquitin chain formation on AKT in an in vitro ubiquitination assay. AKT ubiquitination by NEDD4-1 in vivo requires plasma membrane binding but not phosphorylation of AKT. Ubiquitination of AKT or pAKT by NEDD4-1 promotes AKT nucleus-oriented translocation. IGF-1 signaling stimulates NEDD4-1-mediated ubiquitination of pAKT but not total AKT. A cancer-derived plasma membrane-philic mutant AKT(E17K) is more effectively ubiquitinated by NEDD4-1 and more efficiently trafficked into the nucleus compared with AKT. This study revealed a novel function of AKT ubiquitination by NEDD4-1 in its nuclear trafficking, a step that contributes to AKT activation process in IGF-1 response. Citation Format: Xinjiang Wang, Chuan-Dong Fan, Michelle A. Lum, Chao Xu, Jennifer D. Black. Ubiquitin-dependent regulation of AKT by NEDD4-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5157. doi:10.1158/1538-7445.AM2013-5157