Research highlights
Cell cycle: Akt Skps through
Nature Reviews Cancer 9, 5 (01 May 2009) | doi:10.1038/nrc2649
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An online version of this research highlight appears on the Signaling Gateway.
Cell cycle progression is regulated in part by the ubiquitylation and degradation of the cyclin-dependent-kinase inhibitor p27.
SKP2 (S-phase kinase-associated protein 2) is a substrate-recognizing subunit of the SCF (SKP1
–CUL1–F-box) E3 ubiquitin ligase that ubiquitylates p27. Indeed, overexpression of SKP2 induces cell cycle entry, and cytoplasmic mislocalization of SKP2 has been detected in human cancers. The regulation of SKP2 localization and its incorporation into the SCF complex remains an area of active investigation. Two complementary studies in Nature Cell Biology now show that Akt-mediated phosphorylation of SKP2 promotes its accumulation in the cytoplasm and increases SCF complex formation, resulting in p27 ubiquitylation and degradation.
CORBISSKP2 is known to be phosphorylated at the G1/S transition of the cell cycle, but the importance of this modification was not clear. Lin et al. found that Akt phosphorylated SKP2 at serine 72 in vivo, which increased SCF complex formation and promoted the ubiquitylation and degradation of p27. Expression of wild-type or phosphomimetic, but not phosphorylation-deficient, SKP2 also increased the proliferation and tumorigenic potential of a prostate cancer cell line.
Gao et al. showed that inhibition of PI3K–Akt signalling decreased SKP2 expression and confirmed that SKP2 was a direct substrate of AKT1, but not AKT2. Interestingly, Akt-mediated phosphorylation of SKP2 at serine 72 stimulated subsequent phosphorylation at serine 75 by casein kinase I. It was known that the E3 ubiquitin ligase complex APC–CDH1 mediates SKP2 destruction, and phosphorylation at both these residues inhibited its interaction with CDH1.
Both groups reported that phosphorylated SKP2 is retained in the cytoplasm. Gao et al. found that phosphorylation of SKP2 impaired its binding to nuclear importin receptors, whereas Lin et al. detected an interaction between phosphorylated SKP2 and the cytoplasmic scaffolding protein 14-3-3
. Importantly, Akt phosphorylation and low expression of PTEN (a PI3K antagonist) correlated with cytoplasmic SKP2 localization in human prostate and colon cancer samples. Pharmacological inhibition of PI3K–Akt signalling blocked SKP2-mediated ubiquitylation of p27, pointing to a potential avenue for therapeutic intervention in human cancer.
These results establish SKP2 as an important link between PI3K–Akt signalling and cell cycle progression. Intriguingly, cytoplasmic mislocalization of SKP2 was important for cell migration — and hence metastasis — independent of the SCF complex or p27 degradation. It will be interesting to determine how SKP2 contributes to cell motility.
Author: Emily J. Chenette1
ORIGINAL RESEARCH PAPER
- Lin, H.-K. et al. Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB Nature Cell Biol. 8 Mar 2009 (doi: 10.1038/ncb1849) | Article |
- Gao, D. et al. Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APC–Cdh1-mediated Skp2 destruction Nature Cell Biol. 8 Mar 2009 (doi 10.1038/ncb1847) | Article |
FURTHER READING
- Frecas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and -TrCP: tipping the scales of cancer. Nature Rev. Cancer 8, 438–449 (2008). | Article |
