Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB Journal Article
| Authors: | Lin, H. K.; Wang, G.; Chen, Z.; Teruya-Feldstein, J.; Liu, Y.; Chan, C. H.; Yang, W. L.; Bromage, H.; Nakayama, K. I.; Nimer, S.; Tempst, P.; Pandolfi, P. P. |
| Article Title: | Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB |
| 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. |
| Keywords: | signal transduction; protein kinase b; s6 kinase; controlled study; protein phosphorylation; human cell; nonhuman; protein function; protein localization; neoplasms; cell proliferation; animal cell; animals; mice; complex formation; protein protein interaction; protein binding; enzyme activation; enzyme activity; phosphorylation; carcinogenesis; evolution, molecular; amino acid sequence; conserved sequence; molecular sequence data; protein transport; proto-oncogene proteins c-akt; pten phosphohydrolase; neoplasm metastasis; immunoprecipitation; cell movement; gene switching; ubiquitin protein ligase e3; rapamycin; genetic conservation; cytosol; migration inhibition; 2 morpholino 8 phenylchromone; s phase kinase associated protein 2; wortmannin; 14-3-3 proteins; phosphoserine; s-phase kinase-associated proteins; skp cullin f-box protein ligases |
| Journal Title: | Nature Cell Biology |
| Volume: | 11 |
| Issue: | 4 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-04-01 |
| Start Page: | 420 |
| End Page: | 432 |
| Language: | English |
| DOI: | 10.1038/ncb1849 |
| PUBMED: | 19270694 |
| PROVIDER: | scopus |
| PMCID: | PMC2830812 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 30 November 2010" - "CODEN: NCBIF" - "Source: Scopus" |
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