Nuclear translocation of Skp2 facilitates its destruction in response to TGFβ signaling

Skp2, a F-box protein that determines the substrate specificity for SCF ubiquitin ligase, has recently been demonstrated to be degraded by Cdh1/APC in response to TGFβ signaling. The TGFβ-induced Skp2 proteolysis results in the stabilization of p27 that is necessary to facilitate TGFβ cytostatic eff...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2011-01, Vol.10 (2), p.285-292
Main Authors: Hu, Dong, Liu, Weijun, Wu, George, Wan, Yong
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Amino Acid Sequence
Anaphase-Promoting Complex-Cyclosome
Animals
Binding
Biology
Bioscience
Cadherins - genetics
Cadherins - metabolism
Calcium
Cancer
Cell
Cell Line
Cell Nucleus - metabolism
Cycle
Cyclin-Dependent Kinase Inhibitor p27 - metabolism
Landes
Mink
Organogenesis
Proteins
S-Phase Kinase-Associated Proteins - genetics
S-Phase Kinase-Associated Proteins - metabolism
Signal Transduction
Transforming Growth Factor beta - pharmacology
Ubiquitin-Protein Ligase Complexes - metabolism
Ubiquitination
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Summary:Skp2, a F-box protein that determines the substrate specificity for SCF ubiquitin ligase, has recently been demonstrated to be degraded by Cdh1/APC in response to TGFβ signaling. The TGFβ-induced Skp2 proteolysis results in the stabilization of p27 that is necessary to facilitate TGFβ cytostatic effect. Previous observation from immunocytochemistry indicates that Cdh1 principally localizes in the nucleus while Skp2 mainly localizes in the cytosol, which leaves us a puzzle on how Skp2 is recognized and then ubiquitylated by Cdh1/APC in response to TGFβ stimulation. Here, we report that Skp2 is rapidly translocated from the cytosol to the nucleus upon the cellular stimulation with TGFβ. Using a combinatorial approach of immunocytochemistry, biochemical-fraction-coupled immunoprecipitation, mutagenesis as well as protein degradation assay, we have demonstrated that the TGFβ-induced Skp2 nucleus translocation is critical for TGFβ cytostatic effect that allows physical interaction between Cdh1 and Skp2 and in turn facilitates the Skp2 ubquitylation by Cdh1/APC. Disruption of nuclear localization motifs on Skp2 stabilizes Skp2 in the presence of TGF-β signaling, which attenuates TGFβ-induced p27 accumulation and antagonizes TGFβ-induced growth inhibition. Our finding reveals a cellular mechanism that facilitates Skp2 ubiquitylation by Cdh1/APC in response to TGFβ.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.10.2.14517