Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression

The PTEN tumor-suppressor is frequently affected in cancer, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden Syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the PI-3-Kinase/AKT pathway. However, PTEN is also found in cell nuclei, but mechanism, function and relevance of nuclear localization have remained unclear. Here we show that nuclear PTEN is essential for tumor-suppression and that import is mediated by its mono-ubiquitination. We show that a lysine-mutant of PTEN, which retains catalytic activity yet causes Cowden Syndrome, fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine-residue as major mono-ubiquitination sites essential for PTEN import. Poly-ubiquitination in contrast, leads to PTEN degradation in the cytoplasm, while nuclear PTEN is stable, antagonizes AKT and causes apoptosis. We thus identify the first cancer-associated mutations of PTEN that target post-translational modification and demonstrate how a discrete molecular mechanism dictates tumor-progression by differentiating between degradation and protection of PTEN.