Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB

Hui Kuan Lin, Guocan Wang, Zhenbang Chen, Julie Teruya-Feldstein, Yan Liu, Chia Hsin Chan, Wei Lei Yang, Hediye Erdjument-Bromage, Keiichi I. Nakayama, Stephen D Nimer, Paul Tempst, Pier Paolo Pandolfi

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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 14-3-3β-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.

Original languageEnglish
Pages (from-to)420-432
Number of pages13
JournalNature Cell Biology
Volume11
Issue number4
DOIs
StatePublished - Mar 9 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Lin, H. K., Wang, G., Chen, Z., Teruya-Feldstein, J., Liu, Y., Chan, C. H., Yang, W. L., Erdjument-Bromage, H., Nakayama, K. I., Nimer, S. D., Tempst, P., & Pandolfi, P. P. (2009). Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nature Cell Biology, 11(4), 420-432. https://doi.org/10.1038/ncb1849