The tumour suppressor PTEN mediates a negative regulation of the E3 ubiquitin-protein ligase Nedd4

Cited 38 time in scopus
Metadata Downloads
Title
The tumour suppressor PTEN mediates a negative regulation of the E3 ubiquitin-protein ligase Nedd4
Author(s)
Y Ahn; Chae Young Hwang; S R Lee; Ki Sun Kwon; C Lee
Bibliographic Citation
Biochemical Journal, vol. 412, no. 2, pp. 331-338
Publication Year
2008
Abstract
The tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10; a phosphatidylinositol 3-phosphatase) is a multifunctional protein deregulated in many types of cancer. It is suggested that a number of proteins that relate with PTEN functionally or physically have not yet been found. In order to search for PTEN-interacting proteins that might be crucial in the regulation of PTEN, we exploited a proteomics-based approach. PTEN-expressing NIH 3T3 cell lysates were used in affinity chromatography and then analysed by LC-ESI-MS/MS (liquid chromatography-electrospray ionization-tandem MS). A total of 93 proteins were identified. Among the proteins identified, we concentrated on the E3 ubiquitin-protein ligase Nedd4 (neural-precursor-cell-expressed, developmentally down-regulated gene 4), and performed subsequent validation experiments using HeLa cells. Nedd4 inhibited PTEN-induced apoptotic cell death and, conversely, the Nedd4 level was down-regulated by PTEN. The down-regulation effect was diminished by a mutation (C124S) in the catalytic site of PTEN. Nedd4 expression was also decreased by a PI3K (phosphoinositide 3-kinase) inhibitor, LY294002, suggesting that the regulation is dependent on the phosphatase-kinase activity of the PTEN-PI3K/Akt pathway. Semi-quantitative real-time PCR analysis revealed that Nedd4 was transcriptionally regulated by PTEN. Thus our results have important implications regarding the roles of PTEN upon the E3 ubquitin ligase Nedd4 as a negative feedback regulator as well as a substrate.
Keyword
apoptosisdevelopmentally down-regulated gene 4 (Nedd4)feedback regulatorMSneural-precursor-cell-expressedphosphatase and tensin homologue deleted on chromosome 10 (PTEN)transcriptional regulation
ISSN
0264-6021
Publisher
Portland Press Ltd
DOI
http://dx.doi.org/10.1042/BJ20071403
Type
Article
Appears in Collections:
Division of Research on National Challenges > Aging Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.