The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization
- Fatemeh Fouladkou†,‡,
- Tamara Landry‡,§,
- Hiroshi Kawabe¶,
- Antje Neeb¶,
- Chen Lu†,
- Nils Brose¶,
- Vuk Stambolic§,‖, and
- Daniela Rotin†,‖
- †Hospital for Sick Children and Biochemistry Department, University of Toronto, MaRS-TMDT, 101 College Street, Toronto, Ontario M5G 1L7, Canada;
- §Ontario Cancer Institute, University Health Network, 610 University Avenue, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada; and
- ¶Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, Göttingen 37075, Germany
-
Communicated by Aaron J. Ciechanover, Technion-Israel Institute of Technology, Bat Galim, Haifa, Israel, April 4, 2008
-
↵ ‡F.F. and T.L. contributed equally to this work. (received for review December 5, 2007)
Abstract
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.
Footnotes
- ‖To whom correspondence may be addressed. E-mail: drotin{at}sickkids.ca or vuks{at}uhnres.utoronto.ca
-
Author contributions: F.F., T.L., V.S., and D.R. designed research; F.F., T.L., and H.K. performed research; H.K., A.N., C.L., N.B., V.S., and D.R. contributed new reagents/analytic tools; F.F., T.L., C.L., V.S., and D.R. analyzed data; and F.F., T.L., V.S., and D.R. wrote the paper.
-
The authors declare no conflict of interest.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0803233105/DCSupplemental.
- © 2008 by The National Academy of Sciences of the USA
