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A new class of cancer-associated PTEN mutations defined by membrane translocation defects

Oncogene volume 34, pages 3737–3743 (2015)Cite this article

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Abstract

Phosphatase and tensin homolog (PTEN), which negatively regulates tumorigenic phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling, is a commonly mutated tumor suppressor. The majority of cancer-associated PTEN mutations block its essential PIP3 phosphatase activity. However, there is a group of clinically identified PTEN mutations that maintain enzymatic activity, and it is unknown how these mutations contribute to tumor pathogenesis. Here, we show that these enzymatically competent PTEN mutants fail to translocate to the plasma membrane where PTEN converts PIP3 to PI(4,5)P2. Artificial membrane tethering of the PTEN mutants effectively restores tumor suppressor activity and represses excess PIP3 signaling in cells. Thus, our findings reveal a novel mechanism of tumorigenic PTEN deficiency.

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Acknowledgements

We thank Dr Todd Waldman (Georgetown University School of Medicine) for lentiviral constructs. The mutation data was obtained from the Sanger Institute Catalogue Of Somatic Mutations In Cancer (COSMIC) web site (http://www.sanger.ac.uk/cosmic).27 This work was supported by NIH grants to MI (GM084015), PND (GM28007 and GM34933), HS (GM089853 and NS084154) and to RP (CA082783 and CA155117).

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Author notes

  1. M Keniry

    Present address: 4Current address: Department of Biology, University of Texas- Pan American, Edinburg, TX, USA.,

Authors and Affiliations

  1. Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H-N Nguyen, J-M Yang Jr, M Rahdar, K F Swaney, H Sesaki, P N Devreotes & M Iijima

  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    M Keniry & R Parsons

  3. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    B H Park

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  1. H-N Nguyen
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Correspondence to P N Devreotes or M Iijima.

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Nguyen, HN., Yang Jr, JM., Rahdar, M. et al. A new class of cancer-associated PTEN mutations defined by membrane translocation defects. Oncogene 34, 3737–3743 (2015). https://doi.org/10.1038/onc.2014.293

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