Ubiquitination regulates PTEN nuclear import and tumor suppression Journal Article


Authors: 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.
Article 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. © 2007 Elsevier Inc. All rights reserved.
Keywords: protein kinase b; controlled study; human tissue; gene mutation; human cell; mutation; nonhuman; neoplasm staging; mutant protein; ubiquitin; protein function; protein analysis; animal cell; mouse; animals; mice; cell survival; cancer susceptibility; disease association; heredity; phosphatase; protein degradation; lipid; protein stability; colonic neoplasms; phosphatidylinositol 3 kinase; cancer inhibition; protein processing; ubiquitination; amino acid sequence; molecular sequence data; cancer cell; tumor suppressor proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; cell membrane; protein transport; pten phosphohydrolase; cytoplasm; active transport, cell nucleus; cell nucleus; mutant proteins; catalysis; tumor growth; glutamic acid; nuclear localization signal; ubiquitin-protein ligases; protein structure, secondary; cowden syndrome; glutamine; polyps; lysine; functional proteomics; hamartoma syndrome, multiple; nuclear import
Journal Title: Cell
Volume: 128
Issue: 1
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2007-01-12
Start Page: 141
End Page: 156
Language: English
DOI: 10.1016/j.cell.2006.11.040
PUBMED: 17218261
PROVIDER: scopus
PMCID: PMC1855245
DOI/URL:
Notes: --- - "Cited By (since 1996): 145" - "Export Date: 17 November 2011" - "CODEN: CELLB" - "Source: Scopus"
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