SCFβ-TRCP-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway
Metrics: PDF 1792 views | HTML 1587 views | ?
Jia Liu1,2,*, Lixin Wan2,*, Pengda Liu2,*, Hiroyuki Inuzuka2, Jiankang Liu1, Zhiwei Wang3, and Wenyi Wei2
1 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, FIST, Xi’an Jiaotong University, Xi’an, China
2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
3 The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, P. R. China
* These authors contributed equally to this work
Zhiwei Wang, email:
Wenyi Wei, email:
Keywords: β-TRCP, NEDD4, degradation, PTEN, Akt, cancer, phosphorylation, ubiquitination, therapy
Received: December 9, 2013 Accepted: January 18, 2014 Published: January 20, 2014
The HECT domain-containing ubiquitin E3 ligase NEDD4 is widely expressed in mammalian tissues and plays a crucial role in governing a wide spectrum of cellular processes including cell growth, tissue development and homeostasis. Recent reports have indicated that NEDD4 might facilitate tumorigenesis through targeted degradation of multiple tumor suppressor proteins including PTEN. However, the molecular mechanism by which NEDD4 stability is regulated has not been fully elucidated. Here we report that SCFβ-TRCP governs NEDD4 protein stability by targeting it for ubiquitination and subsequent degradation in a Casein Kinase-I (CKI) phosphorylation-dependent manner. Specifically, depletion of β-TRCP, or inactivation of CKI, stabilized NEDD4, leading to down-regulation of its ubiquitin target PTEN and subsequent activation of the mTOR/Akt oncogenic pathway. Furthermore, we found that CKIδ-mediated phosphorylation of Ser347 and Ser348 on NEDD4 promoted its interaction with SCFβ-TRCP for subsequent ubiquitination and degradation. As a result, compared to ectopic expression of wild-type NEDD4, introducing a non-degradable NEDD4 (S347A/S348A-NEDD4) promoted cancer cell growth and migration. Hence, our findings revealed the CKI/SCFβ-TRCP signaling axis as the upstream negative regulator of NEDD4, and further suggested that enhancing NEDD4 degradation, presumably with CKI or SCFβ-TRCP agonists, could be a promising strategy for treating human cancers.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.