Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization

Oncogene. 2017 Jun 29;36(26):3673-3685. doi: 10.1038/onc.2016.493. Epub 2017 Mar 6.


PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity. Cellular and biochemical analyses as well as structural modelling revealed that two mutations disrupt intramolecular interaction of PTEN and open its conformation, enhancing polyubiquitination of PTEN and decreasing protein stability. Moreover, promoting mono-ubiquitination increases protein stability and nuclear localization of mutant PTEN. Thus, our findings provide a molecular mechanism for cancer-associated PTEN defects and may lead to a brain cancer treatment that targets PTEN mono-ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / enzymology
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • HEK293 Cells
  • Humans
  • Mutation
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism*
  • Protein Stability
  • Signal Transduction
  • Ubiquitination / genetics*


  • PTEN Phosphohydrolase
  • PTEN protein, human