TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=33845977965&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2006.11.040
DO - 10.1016/j.cell.2006.11.040
M3 - Article
C2 - 17218261
AN - SCOPUS:33845977965
VL - 128
SP - 141
EP - 156
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -
