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Tumorigenesis

PTEN — a new guardian of the genome

Nature Reviews Cancer volume 7, pages 162–163 (2007)Cite this article

PTEN is a plasma-membrane lipid phosphatase that antagonizes the function of the phosphatidylinositol 3-kinase (PI3K)–AKT/protein kinase B (PKB) pathway. Various mutations in PTEN have been associated with primary tumours, and an inherited PTEN mutation causes Cowden syndrome — patients with this mutation have an increased risk of tumour development. Although this protein has been extensively studied, there are some unresolved questions. For example, some PTEN mutations occur in regions other than the phosphatase domain, which indicates that PTEN might have other functions in addition to the regulation of PI3K signalling. Intriguingly, this plasma-membrane phosphatase has also been found in cell nuclei, so what is the mechanism and function of this nuclear translocation?

Wang et al. showed that PTEN is ubiquitylated in vitro and in vivo, and purified its ubiquitin ligase as HECT-domain protein NEDD4-1. Although NEDD4-1 alone was not oncogenic, its overexpression increased the efficiency of Ras-mediated transformation of Trp53-deficient mouse embryonic fibroblasts. Further analysis indicated that the aberrant upregulation of NEDD4-1 can post-translationally suppress PTEN activity in human and mouse cancer samples. The authors propose that NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN through ubiquitylation, a paradigm that is analogous to that of MDM2 and p53.

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References

ORIGINAL RESEARCH PAPERS

  1. Wang, X. et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128, 129–139 (2007)

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  2. Trotman, L. C. et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128, 141–156 (2007)

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  3. Shen, W. -H. et al. Essential roles for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007)

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FURTHER READING

  1. Baker S. J. PTEN enters the nuclear age. Cell 128, 25–28 (2007)

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Authors and Affiliations

  1. Associate Editor, Nature Reviews Molecular Cell Biology,

    Ekat Kritikou

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  1. Ekat Kritikou
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Kritikou, E. PTEN — a new guardian of the genome. Nat Rev Cancer 7, 162–163 (2007). https://doi.org/10.1038/nrc2096

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