Journal
ONCOTARGET
Volume 5, Issue 4, Pages 1026-1036Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1675
Keywords
beta-TRCP; NEDD4; degradation; PTEN; Akt; cancer; phosphorylation; ubiquitination; therapy
Categories
Funding
- National Institute of General Medicine, NIH [GM089763, GM094777, CA177910]
- American Cancer Society Scholar
- Leukemia and Lymphoma Society Research Scholar
- [5T32HL007893]
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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 SCF beta-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 beta-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 CKI delta-mediated phosphorylation of Ser347 and Ser348 on NEDD4 promoted its interaction with SCF beta-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/SCF beta-TRCP signaling axis as the upstream negative regulator of NEDD4, and further suggested that enhancing NEDD4 degradation, presumably with CKI or SCF beta-TRCP agonists, could be a promising strategy for treating human cancers.
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