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Substrate Recognition and Ubiquitination of SCFSkp2/Cks1 Ubiquitin-Protein Isopeptide Ligase

p27, an important cell cycle regulator, blocks the G1/S transition in cells by binding and inhibiting Cdk2/cyclin A and Cdk2/cyclin E complexes (Cdk2/E). Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evid...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-05, Vol.282 (21), p.15462-15470
Main Authors: Xu, Shuichan, Abbasian, Mahan, Patel, Palka, Jensen-Pergakes, Kristen, Lombardo, Christian R., Cathers, Brian E., Xie, Weilin, Mercurio, Frank, Pagano, Michele, Giegel, David, Cox, Sarah
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Language:English
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Summary:p27, an important cell cycle regulator, blocks the G1/S transition in cells by binding and inhibiting Cdk2/cyclin A and Cdk2/cyclin E complexes (Cdk2/E). Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both Cdk2/E and phosphorylation of Thr187 on p27 are essential for the recognition of p27 by the SCFSkp2/Cks1 complex, the ubiquitin-protein isopeptide ligase (E3). Cdk2/E provides a high affinity binding site, whereas the phosphorylated Thr187 provides a low affinity binding site for the Skp2/Cks1 complex. Furthermore, binding of phosphorylated p27/Cdk2/E to the E3 complex showed positive cooperativity. Consistently, p27 is also ubiquitinated in a similarly cooperative manner. In the absence of p27, Cdk2/E and Cks1 increase Skp2 phosphorylation. This phosphorylation enhances Skp2 auto-ubiquitination, whereas p27 inhibits both phosphorylation and auto-ubiquitination of Skp2.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M610758200