TY - JOUR
T1 - Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB
AU - Lin, Hui Kuan
AU - Wang, Guocan
AU - Chen, Zhenbang
AU - Teruya-Feldstein, Julie
AU - Liu, Yan
AU - Chan, Chia Hsin
AU - Yang, Wei Lei
AU - Erdjument-Bromage, Hediye
AU - Nakayama, Keiichi I.
AU - Nimer, Stephen
AU - Tempst, Paul
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We thank D. Bohmann, P. Jackson, W. Wei, M. Pagano and M. H. Lee for reagents. We are also grateful to M. Asherov and I. Linkov in the Immunohistochemistry Pathology Core Laboratory, T. Matos for immunohistochemistry technical assistance, P. Bonner for data management, L. Lacomis for help with mass spectrometry, X. H. Zhu for technical advice, and S. Clohessy for flow cytometry analysis. We also thank M. C. Hung and L. Cantley for insightful comments and suggestions, and W. Wei for discussion and for sharing experimental results. Special thanks are extended to B. Carver and L. DiSantis for editing and critical reading of the manuscript, as well as to all the members of the Pandolfi laboratory for comments and discussion. This work was supported by NIH grants RO1 CA-71692 and CA-74031 to P.P.P. and by M. D. Anderson Cancer Center Trust Scholar funds to H.K.L. The Microchemistry & Proteomics Core is supported by NIH grant P30 CA-08748.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1038/ncb1849
DO - 10.1038/ncb1849
M3 - Article
C2 - 19270694
AN - SCOPUS:64049087382
SN - 1465-7392
VL - 11
SP - 420
EP - 432
JO - Nature cell biology
JF - Nature cell biology
IS - 4
ER -