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1: Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8585-90. Epub 2008 Jun 18.
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The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization.

Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N, Stambolic V, Rotin D.

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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PMID: 18562292 [PubMed - indexed for MEDLINE]

PMCID: PMC2438405 [Available on 12/24/08]