Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Beta-TrCP, the F-box protein of the SCF(beta-TrCP) ubiquitin ligase (SCF, Skp1/Cul1/F-box protein), recognizes the doubly phosphorylated DSG motif (DpSGPhiXpS) in various SCF(beta-TrCP) target proteins. The Cdc25A phosphatase, a key cell-cycle regulator in vertebrate cells, undergoes a rapid ubiquitin-dependent degradation in response to genotoxic stress. Beta-TrCP binds to the DSG motif of human Cdc25A in a manner dependent on Chk1 and other unknown kinases. However, Xenopus Cdc25A does not have a DSG motif at the corresponding site of human Cdc25A. Here, we report that both Xenopus Cdc25A and human Cdc25A have a previously undescribed nonphosphorylated DDG motif (DDGPhiXD) for recognition by beta-TrCP. When analyzed by using Xenopus eggs, the binding of beta-TrCP to the DDG motif is essential for the Chk1-induced ubiquitination and degradation of Xenopus Cdc25A and also plays a role in the degradation of human Cdc25A. The DDG motif also exists in human Cdc25B phosphatase (another key cell-cycle regulator), binds beta-TrCP strongly, and is essential for the ubiquitination and degradation of the (labile) phosphatase in normal conditions. We provide strong evidence that, in both Cdc25A and Cdc25B, the binding (efficiency) of beta-TrCP to the DDG motif is regulated by nearby residues, while ubiquitination is regulated by other events in addition to the beta-TrCP binding. Finally, our additional data suggest that beta-TrCP may recognize nonphosphorylated DDG-like motifs in many other proteins, including X11L (a putative suppressor of beta-amyloid production) and hnRNP-U (a pseudosubstrate of SCF(beta-TrCP)).
Baldin,
Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation.
1997, Pubmed
Baldin,
Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation.
1997,
Pubmed
Besnard-Guerin,
HIV-1 Vpu sequesters beta-transducin repeat-containing protein (betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin and other SCFbetaTrCP substrates.
2004,
Pubmed
Busino,
Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.
2003,
Pubmed
Busino,
Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis.
2004,
Pubmed
Cardozo,
The SCF ubiquitin ligase: insights into a molecular machine.
2004,
Pubmed
Davis,
Pseudosubstrate regulation of the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U.
2002,
Pubmed
Deshaies,
SCF and Cullin/Ring H2-based ubiquitin ligases.
1999,
Pubmed
Donzelli,
Regulating mammalian checkpoints through Cdc25 inactivation.
2003,
Pubmed
Donzelli,
Dual mode of degradation of Cdc25 A phosphatase.
2002,
Pubmed
Falck,
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.
2001,
Pubmed
Fuchs,
The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer.
2004,
Pubmed
Gabrielli,
Hyperphosphorylation of the N-terminal domain of Cdc25 regulates activity toward cyclin B1/Cdc2 but not cyclin A/Cdk2.
1997,
Pubmed
Jin,
SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase.
2003,
Pubmed
Kim,
A maternal form of the phosphatase Cdc25A regulates early embryonic cell cycles in Xenopus laevis.
1999,
Pubmed
,
Xenbase
Kitagawa,
An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.
1999,
Pubmed
Lammer,
The cdc25B phosphatase is essential for the G2/M phase transition in human cells.
1998,
Pubmed
Liu,
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
2002,
Pubmed
,
Xenbase
Mailand,
Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability.
2002,
Pubmed
Mailand,
Rapid destruction of human Cdc25A in response to DNA damage.
2000,
Pubmed
Maniatis,
A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways.
1999,
Pubmed
Mantovani,
Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor.
2003,
Pubmed
Margottin-Goguet,
Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.
2003,
Pubmed
,
Xenbase
Molinari,
Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis.
2000,
Pubmed
Moshe,
Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome.
2004,
Pubmed
,
Xenbase
Nishijima,
A dual-specificity phosphatase Cdc25B is an unstable protein and triggers p34(cdc2)/cyclin B activation in hamster BHK21 cells arrested with hydroxyurea.
1997,
Pubmed
Oe,
Cytoplasmic occurrence of the Chk1/Cdc25 pathway and regulation of Chk1 in Xenopus oocytes.
2001,
Pubmed
,
Xenbase
Okazaki,
Isolation of a cDNA encoding the X enopus homologue of mammalian Cdc25A that can induce meiotic maturation of oocytes.
1996,
Pubmed
,
Xenbase
Orian,
SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase.
2000,
Pubmed
Rechsteiner,
PEST sequences and regulation by proteolysis.
1996,
Pubmed
Sagata,
Molecular biology. Untangling checkpoints.
2002,
Pubmed
,
Xenbase
Schulman,
Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex.
2000,
Pubmed
Shimuta,
Chk1 is activated transiently and targets Cdc25A for degradation at the Xenopus midblastula transition.
2002,
Pubmed
,
Xenbase
Sørensen,
Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.
2003,
Pubmed
Suzuki,
IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2.
1999,
Pubmed
Taru,
Facilitation of stress-induced phosphorylation of beta-amyloid precursor protein family members by X11-like/Mint2 protein.
2004,
Pubmed
Uto,
Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism.
2004,
Pubmed
,
Xenbase
Watanabe,
M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.
2004,
Pubmed
Winston,
The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.
1999,
Pubmed
Wu,
Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase.
2003,
Pubmed
Yaron,
Identification of the receptor component of the IkappaBalpha-ubiquitin ligase.
1998,
Pubmed
Zhao,
Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.
2002,
Pubmed
Zhou,
Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition.
2004,
Pubmed
