Abstract
PTEN, a lipid phosphatase, is one of the most frequently mutated tumour suppressors in human cancer. Several recent studies have highlighted the importance of ubiquitylation in regulating PTEN tumour-suppressor function, but the enzymatic machinery required for PTEN ubiquitylation is not clear. In this study, by using a tandem affinity-purification approach, we have identified WWP2 (also known as atrophin-1-interacting protein 2, AIP-2) as a PTEN-interacting protein. WWP2 is an E3 ubiquitin ligase that belongs to the NEDD4-like protein family, which is involved in regulating transcription, embryonic stem-cell fate, cellular transport and T-cell activation processes. We show that WWP2 physically interacts with PTEN and mediates its degradation through a ubiquitylation-dependent pathway. Functionally, we show that WWP2 controls cellular apoptosis and is required for tumorigenicity of cells. Collectively, our results reveal a functional E3 ubiquitin ligase for PTEN that plays a vital role in tumour-cell survival.
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Acknowledgements
This work was supported in part by a grant from the Department of Biotechnology, Ministry of Science and Technology, India (to S.M.; BT/PR13134/GBD/27/202/2009), an Era of Hope Research Scholar Award (to J.C.; W81XWH-09-0409) and an NIH SPORE award (to J.N.S.; CA108961). J.C. is the recipient of an Era of Hope Scholar award from the Department of Defense (W81XWH-05-0470) and a member of MD Anderson Cancer Center (CA016672). S.K., N.R. and V.R.P. acknowledge fellowship support from the Department of Biotechnology, Council of Scientific and Industrial Research and University Grants Commission, India, respectively. S.M. is a recipient of the Department of Biotechnology’s IYBA award. We also acknowledge the Institute of Life Sciences, Hyderabad, for providing basic support during some parts of this work.
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S.M., S.K., N.R. and V.R.P. carried out most of the experiments. J.L.P. and J.N.S. carried out the in vivo xenograft experiments. S.M. and J.C. designed the experiments, analysed the data and wrote the manuscript.
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Maddika, S., Kavela, S., Rani, N. et al. WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol 13, 728–733 (2011). https://doi.org/10.1038/ncb2240
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DOI: https://doi.org/10.1038/ncb2240
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