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

doi:10.1016/j.cell.2006.11.040

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 journal › Article › peer-review

635 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	141-156
Number of pages	16
Journal	Cell
Volume	128
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2006.11.040
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2006.11.040

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Trotman, L. C., Wang, X., Alimonti, A., Chen, Z., Teruya-Feldstein, J., Yang, H., Pavletich, N. P., Carver, B. S., Cordon-Cardo, C., Erdjument-Bromage, H., Tempst, P., Chi, S. G., Kim, H. J., Misteli, T., Jiang, X., & Pandolfi, P. P. (2007). Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression. Cell, 128(1), 141-156. https://doi.org/10.1016/j.cell.2006.11.040

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title = "Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression",

abstract = "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.",

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

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. ",

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doi = "10.1016/j.cell.2006.11.040",

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T1 - Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression

AU - Trotman, Lloyd C.

AU - Wang, Xinjiang

AU - Alimonti, Andrea

AU - Chen, Zhenbang

AU - Teruya-Feldstein, Julie

AU - Yang, Haijuan

AU - Pavletich, Nikola P.

AU - Carver, Brett S.

AU - Cordon-Cardo, Carlos

AU - Erdjument-Bromage, Hediye

AU - Tempst, Paul

AU - Chi, Sung Gil

AU - Kim, Hyo Jong

AU - Misteli, Tom

AU - Jiang, Xuejun

AU - Pandolfi, Pier Paolo

N1 - 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.

PY - 2007/1/12

Y1 - 2007/1/12

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cell.2006.11.040

DO - 10.1016/j.cell.2006.11.040

M3 - Article

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SN - 0092-8674

VL - 128

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EP - 156

JO - Cell

JF - Cell

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ER -

Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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