Ubiquitination regulates PTEN nuclear import and tumor suppression.
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.
Trotman
Lloyd C
LC
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Wang
Xinjiang
X
Alimonti
Andrea
A
Chen
Zhenbang
Z
Teruya-Feldstein
Julie
J
Yang
Haijuan
H
Pavletich
Nikola P
NP
Carver
Brett S
BS
Cordon-Cardo
Carlos
C
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Chi
Sung-Gil
SG
Kim
Hyo-Jong
HJ
Misteli
Tom
T
Jiang
Xuejun
X
Pandolfi
Pier Paolo
PP
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport; D005973:Glutamine / Q000235:genetics; D006223:Hamartoma Syndrome, Multiple / Q000473:pathology; D006801:Humans; D008239:Lysine / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D000075702:Nedd4 Ubiquitin Protein Ligases; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000378:metabolism*; D011127:Polyps / Q000473:pathology; D017433:Protein Structure, Secondary; D021381:Protein Transport; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D005973:Glutamine; D000075702:Nedd4 Ubiquitin Protein Ligases; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; D008239:Lysine