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.
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Abbreviations
- PTEN:
-
phosphatase and tensin homolog
- NEDD4-1:
-
neural precursor cell expressed developmentally downregulated protein 4-1
- HECT:
-
homologous to the E6-AP carboxyl terminus
- PI3K:
-
phosphatidylinositol 3-kinase
- XIAP:
-
X-linked inhibitor of apoptosis protein
- MEF:
-
mouse embryonic fibroblast
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Acknowledgements
This work was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), which was funded by the Ministry of Education, Science and Technology (2012009160), and a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare and Family Affairs, Republic of Korea (A062254). This work also was supported by Grant 2012-231 from the Asan Institute for Life Sciences, Seoul, Republic of Korea. We thank Dr. Colin S Duckett (University of Michigan Medical School) for providing the XIAP−/− MEFs. We would like to thank Professor Kyoung Tai No for allowing to access the computational resources in his group.
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Hong, SW., Moon, JH., Kim, JS. et al. p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN. Cell Death Differ 21, 146–160 (2014). https://doi.org/10.1038/cdd.2013.141
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DOI: https://doi.org/10.1038/cdd.2013.141
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