Article abstract
Nature Cell Biology 11, 420 - 432 (2009)
Published online: 8 March 2009 | doi:10.1038/ncb1849
Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB
Hui-Kuan Lin1,3, Guocan Wang1,2, Zhenbang Chen1,2,7, Julie Teruya-Feldstein1, Yan Liu4, Chia-Hsin Chan3, Wei-Lei Yang3, Hediye Erdjument-Bromage5, Keiichi I. Nakayama6, Stephen Nimer4, Paul Tempst5 & Pier Paolo Pandolfi1,2
Abstract
Skp2 is an F-box protein that forms the SCF complex with Skp1 and Cullin-1 to constitute an E3 ligase for ubiquitylation. Ubiquitylation and degradation of the p27 are critical for Skp2-mediated entry to the cell cycle, and overexpression and cytosolic accumulation of Skp2 have been clearly associated with tumorigenesis, although the functional significance of the latter is still unknown. Here we show that Akt/protein kinase B (PKB) interacts with and directly phosphorylates Skp2. We find that Skp2 phosphorylation by Akt triggers SCF complex formation and E3 ligase activity. A phosphorylation-defective Skp2 mutant is drastically impaired in its ability to promote cell proliferation and tumorigenesis. Furthermore, we show that Akt-mediated phosphorylation triggers 14-3-3
-dependent Skp2 relocalization to the cytosol, and we attribute a specific role to cytosolic Skp2 in the positive regulation of cell migration. Finally, we demonstrate that high levels of activation of Akt correlate with the cytosolic accumulation of Skp2 in human cancer specimens. Our results therefore define a novel proto-oncogenic Akt/PKB-dependent signalling pathway.
- Cancer Biology and Genetics Program, Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
- Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
- Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
- Molecular Pharmacology and Chemistry Program,
- Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
- Present address: Department of Cancer Biology, Meharry Medical College, 1005 Dr D. B. Todd Jr Boulevard, Nashville, Tennessee 37067-3599, USA.
Correspondence to: Pier Paolo Pandolfi1,2 e-mail: ppandolf@bidmc.harvard.edu
Correspondence to: Hui-Kuan Lin1,3 e-mail: hklin@mdanderson.org
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Skp2: caught in the AktNature Cell Biology News and Views (01 Apr 2009)
Kip1 meets SKP2: new links in cell-cycle controlNature Cell Biology News and Views (01 Aug 1999)
See all 3 matches for News And ViewsRESEARCH
Evidence for Cytosolic p27(Kip1) Ubiquitylation and Degradation during Adipocyte Hyperplasia *Obesity Original Article
Evidence for Cytosolic p27(Kip1) Ubiquitylation and Degradation during Adipocyte Hyperplasia *Obesity Original Article
See all 23 matches for Research
