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Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8585-90. doi: 10.1073/pnas.0803233105. Epub 2008 Jun 18.

The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization.

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Hospital for Sick Children and Biochemistry Department, University of Toronto, MaRS-TMDT, 101 College Street, Toronto, Ontario M5G 1L7, Canada.


PTEN is a tumor suppressor frequently mutated in cancer. Recent reports implicated Nedd4-1 as the E3 ubiquitin ligase for PTEN that regulates its stability and nuclear localization. We tested the physiological role of Nedd4-1 as a PTEN regulator by using cells and tissues derived from two independently generated strains of mice with their Nedd4-1 gene disrupted. PTEN stability and ubiquitination were indistinguishable between the wild-type and Nedd4-1-deficient cells, and an interaction between the two proteins could not be detected. Moreover, PTEN subcellular distribution, showing prominent cytoplasmic and nuclear staining, was independent of Nedd4-1 presence. Finally, activation of PKB/Akt, a major downstream target of cytoplasmic PTEN activity, and the ability of PTEN to transactivate the Rad51 promoter, a measure of its nuclear function, were unaffected by the loss of Nedd4-1. Taken together, our results fail to support a role for Nedd4-1 as the E3 ligase regulating PTEN stability and subcellular localization.

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