Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression

Lloyd C. Trotman, Xinjiang Wang, Andrea Alimonti, Zhenbang Chen, Julie Teruya-Feldstein, Haijuan Yang, Nikola P. Pavletich, Brett S. Carver, Carlos Cordon-Cardo, Hediye Erdjument-Bromage, Paul Tempst, Sung Gil Chi, Hyo Jong Kim, Tom Misteli, Xuejun Jiang, Pier Paolo Pandolfi

Research output: Contribution to journalArticlepeer-review

616 Citations (Scopus)


The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN.

Original languageEnglish
Pages (from-to)141-156
Number of pages16
Issue number1
Publication statusPublished - 2007 Jan 12

Bibliographical note

Funding Information:
We would like to thank Q. Li, S. Mabon, and M.S. Jiao for help with insect cell culture, FRAP, and pathology analysis, respectively. We would like to thank P. Bonner for data management, L. Lopez and E. Iskidarova for technical assistance in tissue microarray construction, I. Linkov and M. Asher and the Pathology Core Laboratory at MSKCC for help with their expertise in IHC, and A. Nazarian for help with MS. This research was supported by the NIH grant R01-CA-82328 to P.P.P. and the NCI Cancer Center Support Grant P30-CA-08748 to P.T. and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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