SCFß-TRCP-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway

Jia Liu, Lixin Wan, Pengda Liu, Hiroyuki Inuzuka, Jiankang Liu, Zhiwei Wang, Wenyi Wei

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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 SCFß-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 ß-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 SCFß-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/SCFß-TRCP signaling axis as the upstream negative regulator of NEDD4, and further suggested that enhancing NEDD4 degradation, presumably with CKI or SCFß-TRCP agonists, could be a promising strategy for treating human cancers.

Original languageEnglish
Pages (from-to)1026-1037
Number of pages12
JournalOncotarget
Volume5
Issue number4
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Akt
  • Cancer
  • Degradation
  • NEDD4
  • PTEN
  • Phosphorylation
  • Therapy
  • Ubiquitination
  • β-TRCP

ASJC Scopus subject areas

  • Oncology

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