Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB.
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 14-3-3beta-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.
Lin
Hui-Kuan
HK
Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. hklin@mdanderson.org
Wang
Guocan
G
Chen
Zhenbang
Z
Teruya-Feldstein
Julie
J
Liu
Yan
Y
Chan
Chia-Hsin
CH
Yang
Wei-Lei
WL
Erdjument-Bromage
Hediye
H
Nakayama
Keiichi I
KI
Nimer
Stephen
S
Tempst
Paul
P
Pandolfi
Pier Paolo
PP
D048948:14-3-3 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D017124:Conserved Sequence; D003600:Cytosol / Q000378:metabolism*; D004789:Enzyme Activation; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism
D048948:14-3-3 Proteins; D044786:S-Phase Kinase-Associated Proteins; D010768:Phosphoserine; D044843:SKP Cullin F-Box Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human