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

Author:

Ahn Younghee12,Hwang Chae Young3,Lee Seung-Rock4,Kwon Ki-Sun3,Lee Cheolju1

Affiliation:

1. Life Sciences Division, Korea Institute of Science and Technology, Seoul 136-791, Korea

2. Center for Cell Signaling Research, Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, Korea

3. Laboratory of Cell Signaling, Omics and Integration Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea

4. Department of Biochemistry, Chonnam National University Medical School, Gwangju 500-757, Korea

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

Reference42 articles.

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5. PTEN enhances TNF-induced apoptosis through modulation of nuclear factor-κB signaling pathway in human glioma cells;Koul;Biochem. Biophys. Res. Commun.,2006

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