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

Jr M. Yang, P. Schiapparelli, H. N. Nguyen, A. Igarashi, Q. Zhang, S. Abbadi, L. M. Amzel, H. Sesaki, Alfredo Quinones-Hinojosa, M. Iijima

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3673-3685
Number of pages13
JournalOncogene
Volume36
Issue number26
DOIs
StatePublished - Jun 29 2017
Externally publishedYes

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Protein Stability
Ubiquitination
Phosphoric Monoester Hydrolases
Brain Neoplasms
PTEN Phosphohydrolase
Mutation
Glioblastoma
Phosphatidylinositol 3-Kinases
Neoplasms
Cell Membrane
Lipids
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Yang, J. M., Schiapparelli, P., Nguyen, H. N., Igarashi, A., Zhang, Q., Abbadi, S., ... Iijima, M. (2017). Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene, 36(26), 3673-3685. https://doi.org/10.1038/onc.2016.493

Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. / Yang, Jr M.; Schiapparelli, P.; Nguyen, H. N.; Igarashi, A.; Zhang, Q.; Abbadi, S.; Amzel, L. M.; Sesaki, H.; Quinones-Hinojosa, Alfredo; Iijima, M.

In: Oncogene, Vol. 36, No. 26, 29.06.2017, p. 3673-3685.

Research output: Contribution to journalArticle

Yang, JM, Schiapparelli, P, Nguyen, HN, Igarashi, A, Zhang, Q, Abbadi, S, Amzel, LM, Sesaki, H, Quinones-Hinojosa, A & Iijima, M 2017, 'Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization', Oncogene, vol. 36, no. 26, pp. 3673-3685. https://doi.org/10.1038/onc.2016.493
Yang, Jr M. ; Schiapparelli, P. ; Nguyen, H. N. ; Igarashi, A. ; Zhang, Q. ; Abbadi, S. ; Amzel, L. M. ; Sesaki, H. ; Quinones-Hinojosa, Alfredo ; Iijima, M. / Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. In: Oncogene. 2017 ; Vol. 36, No. 26. pp. 3673-3685.
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