NEDD4L protein catalyzes ubiquitination of PIK3CA protein and regulates PI3K-AKT signaling

Zixi Wang, Tingting Dang, Tingting Liu, She Chen, Lin Li, Song Huang, Min Fang

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogenic PIK3CA (p110α), the catalytic subunit of class IA PI3K, plays a major role in PI3K-related cancer progression. The mechanisms underlying the dynamic regulation of PIK3CA protein levels remain unknown. Here we demonstrated that PIK3CA is regulated by polyubiquitination. We identified NEDD4L as the E3 ligase that catalyzes PIK3CA polyubiquitination, leading to its proteasome-dependent degradation. NEDD4L ubiquitinates both the free and regulatory subunitbound PIK3CA but does not ubiquitinate the regulatory subunit of PI3K. Overexpression of NEDD4L accelerates the turnover rate of PIK3CA, whereas suppression of NEDD4L results in not only the accumulation of PIK3CA but also a paradoxical decrease of AKT activation. Thus, we propose that NEDD4L negatively regulates PIK3CA protein levels via ubiquitination and is required for the maintenance of PI3K-AKT signaling pathway.

Original languageEnglish (US)
Pages (from-to)17467-17477
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number33
DOIs
StatePublished - Aug 12 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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