Ubiquitination regulates PTEN nuclear import and tumor suppression

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. (January 2007) Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell, 128 (1). pp. 141-56.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/17218261
DOI: 10.1016/j.cell.2006.11.040

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.

Item Type: Paper
Additional Information: 0092-8674 (Print) Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural
Uncontrolled Keywords: *Active Transport, Cell Nucleus Amino Acid Sequence Animals Cell Nucleus/*metabolism Colonic Neoplasms/pathology Glutamine/genetics Hamartoma Syndrome, Multiple/pathology Humans Lysine/genetics Mice Molecular Sequence Data Mutant Proteins/chemistry/metabolism Mutation/genetics Neoplasm Staging PTEN Phosphohydrolase/chemistry/*metabolism Polyps/pathology Protein Structure, Secondary Protein Transport Tumor Suppressor Proteins/*metabolism Ubiquitin/*metabolism Ubiquitin-Protein Ligases/metabolism
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: CSHL Librarian
Date: 12 January 2007
Date Deposited: 01 Nov 2011 19:02
Last Modified: 08 May 2013 16:34
PMCID: PMC1855245
Related URLs:
URI: http://repository.cshl.edu/id/eprint/23159

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