| Literature DB >> 27339899 |
Zixi Wang1, Tingting Dang1, Tingting Liu1, She Chen2, Lin Li2, Song Huang2, Min Fang3.
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 subunit-bound 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.Entities:
Keywords: Akt PKB; E3 ubiquitin ligase; NEDD4L; PIK3CA; phosphatidylinositide 3-kinase (PI 3-kinase); proteasome; protein degradation; ubiquitylation (ubiquitination)
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Year: 2016 PMID： 27339899 PMCID： PMC5016142 DOI： 10.1074/jbc.M116.726083
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157