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The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1.
Pfleger CM
,
Kirschner MW
.
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The ordered progression through the cell cycle depends on regulating the abundance of several proteins through ubiquitin-mediated proteolysis. Degradation is precisely timed and specific. One key component of the degradation system, the anaphase promoting complex (APC), is a ubiquitin protein ligase. It is activated both during mitosis and late in mitosis/G(1), by the WD repeat proteins Cdc20 and Cdh1, respectively. These activators target distinct sets of substrates. Cdc20-APC requires a well-defined destruction box (D box), whereas Cdh1-APC confers a different and as yet unidentified specificity. We have determined the sequence specificity for Cdh1-APC using two assays, ubiquitination in a completely defined and purified system and degradation promoted by Cdh1-APC in Xenopus extracts. Cdc20 is itself a Cdh1-APC substrate. Vertebrate Cdc20 lacks a D box and therefore is recognized by Cdh1-APC through a different sequence. By analysis of Cdc20 as a substrate, we have identified a new recognition signal. This signal, composed of K-E-N, serves as a general targeting signal for Cdh1-APC. Like the D box, it is transposable to other proteins. Using the KEN box as a template, we have identified cell cycle genes Nek2 and B99 as additional Cdh1-APC substrates. Mutation in the KEN box stabilizes all three proteins against ubiquitination and degradation.
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10733526
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Bischoff,
The Aurora/Ipl1p kinase family: regulators of chromosome segregation and cytokinesis.
1999, Pubmed
Bischoff,
The Aurora/Ipl1p kinase family: regulators of chromosome segregation and cytokinesis.
1999,
Pubmed
Ciechanover,
The ubiquitin-proteasome proteolytic pathway.
1994,
Pubmed
Cohen-Fix,
Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p.
1996,
Pubmed
,
Xenbase
Coux,
Structure and functions of the 20S and 26S proteasomes.
1996,
Pubmed
Fang,
Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1.
1998,
Pubmed
,
Xenbase
Fuchs,
HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin.
1999,
Pubmed
Funabiki,
Cut2 proteolysis required for sister-chromatid seperation in fission yeast.
1996,
Pubmed
Gieffers,
Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons.
1999,
Pubmed
Glotzer,
Cyclin is degraded by the ubiquitin pathway.
1991,
Pubmed
,
Xenbase
Goldberg,
Proteolysis, proteasomes and antigen presentation.
1992,
Pubmed
Hochstrasser,
Protein degradation or regulation: Ub the judge.
1996,
Pubmed
Holloway,
Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor.
1993,
Pubmed
,
Xenbase
Irniger,
The anaphase-promoting complex is required in G1 arrested yeast cells to inhibit B-type cyclin accumulation and to prevent uncontrolled entry into S-phase.
1997,
Pubmed
Juang,
APC-mediated proteolysis of Ase1 and the morphogenesis of the mitotic spindle.
1997,
Pubmed
King,
Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates.
1996,
Pubmed
,
Xenbase
Klotzbücher,
The 'destruction box' of cyclin A allows B-type cyclins to be ubiquitinated, but not efficiently destroyed.
1996,
Pubmed
Kotani,
Regulation of APC activity by phosphorylation and regulatory factors.
1999,
Pubmed
Kumar,
Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity.
1997,
Pubmed
Lorca,
Fizzy is required for activation of the APC/cyclosome in Xenopus egg extracts.
1998,
Pubmed
,
Xenbase
Mahaffey,
Ubiquitin metabolism in cycling Xenopus egg extracts.
1993,
Pubmed
,
Xenbase
Margottin,
A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif.
1998,
Pubmed
McGarry,
Geminin, an inhibitor of DNA replication, is degraded during mitosis.
1998,
Pubmed
,
Xenbase
Murray,
Cyclin synthesis drives the early embryonic cell cycle.
1989,
Pubmed
,
Xenbase
Murray,
Cell cycle extracts.
1991,
Pubmed
Peters,
SCF and APC: the Yin and Yang of cell cycle regulated proteolysis.
1998,
Pubmed
Prinz,
The regulation of Cdc20 proteolysis reveals a role for APC components Cdc23 and Cdc27 during S phase and early mitosis.
1998,
Pubmed
Rogers,
Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis.
1986,
Pubmed
Scheffner,
Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade.
1995,
Pubmed
Scheffner,
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53.
1993,
Pubmed
Schultz,
Cell cycle-dependent expression of Nek2, a novel human protein kinase related to the NIMA mitotic regulator of Aspergillus nidulans.
1994,
Pubmed
Schwab,
Yeast Hct1 is a regulator of Clb2 cyclin proteolysis.
1997,
Pubmed
Shirayama,
The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae.
1998,
Pubmed
Utrera,
A novel p53-inducible gene coding for a microtubule-localized protein with G2-phase-specific expression.
1998,
Pubmed
Visintin,
CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.
1997,
Pubmed
Weinstein,
Cell cycle-regulated expression, phosphorylation, and degradation of p55Cdc. A mammalian homolog of CDC20/Fizzy/slp1.
1997,
Pubmed
Wolf,
Cell cycle: oiling the gears of anaphase.
1998,
Pubmed
Yamamoto,
Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s).
1996,
Pubmed
Yaron,
Identification of the receptor component of the IkappaBalpha-ubiquitin ligase.
1998,
Pubmed
Zachariae,
Whose end is destruction: cell division and the anaphase-promoting complex.
1999,
Pubmed
Zou,
Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis.
1999,
Pubmed
,
Xenbase
