p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN

S-W Hong; J-H Moon; J-S Kim; J-S Shin; K-A Jung; W-K Lee; S-Y Jeong; J J Hwang; S-J Lee; Y-A Suh; I Kim; K-Y Nam; S Han; J E Kim; K-P Kim; Y S Hong; J-L Lee; W-J Lee; E K Choi; J S Lee; D-H Jin; T W Kim

doi:10.1038/cdd.2013.141

p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN

Cell Death Differ. 2014 Jan;21(1):146-60. doi: 10.1038/cdd.2013.141. Epub 2013 Oct 18.

Authors

S-W Hong¹, J-H Moon, J-S Kim, J-S Shin, K-A Jung, W-K Lee, S-Y Jeong, J J Hwang, S-J Lee, Y-A Suh, I Kim, K-Y Nam, S Han, J E Kim, K-P Kim, Y S Hong, J-L Lee, W-J Lee, E K Choi, J S Lee, D-H Jin, T W Kim

Affiliation

¹ 1] Innovative Cancer Research, Asan Medical Center, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul, Republic of Korea [2] Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Abstract

PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation
Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / metabolism*
HEK293 Cells
Humans
MCF-7 Cells
Nedd4 Ubiquitin Protein Ligases
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism*
Protein Stability
Protein Structure, Tertiary
RNA Interference
RNA, Small Interfering / metabolism
Trans-Activators / antagonists & inhibitors
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription Factors
Ubiquitin-Protein Ligases / antagonists & inhibitors
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

Endosomal Sorting Complexes Required for Transport
Nuclear Proteins
RNA, Small Interfering
SERTAD1 protein, human
Trans-Activators
Transcription Factors
Nedd4 Ubiquitin Protein Ligases
Nedd4 protein, human
Ubiquitin-Protein Ligases
PTEN Phosphohydrolase