Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.
Progression through mitosis occurs because cyclin B/Cdc2 activation induces the anaphase promoting complex (APC) to cause cyclin B destruction and mitotic exit. To ensure that cyclin B/Cdc2 does not prematurely activate the APC in early mitosis, there must be a mechanism delaying APC activation. Emi1 is a protein capable of inhibiting the APC in S and G2. We show here that Emi1 is phosphorylated by Cdc2, and on a DSGxxS consensus site, is subsequently recognized by the SCF(betaTrCP/Slimb) ubiquitin ligase and destroyed, thus providing a delay for APC activation. Failure of betaTrCP-dependent Emi1 destruction stabilizes APC substrates and results in mitotic catastrophe including centrosome overduplication, potentially explaining mitotic deficiencies in Drosophila Slimb/betaTrCP mutants. We hypothesize that Emi1 destruction relieves a late prophase checkpoint for APC activation.
Margottin-Goguet
Florence
F
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Hsu
Jerry Y
JY
Loktev
Alexander
A
Hsieh
Harn Mei
HM
Reimann
Julie D R
JD
Jackson
Peter K
PK
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D016384:Consensus Sequence; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D029721:Drosophila Proteins; D004789:Enzyme Activation; D044783:F-Box Proteins; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation; D015739:Nocodazole / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D010453:Peptide Synthases / Q000378:metabolism*; D010766:Phosphorylation; D044843:SKP Cullin F-Box Protein Ligases; D013552:Swine; D013997:Time Factors; D014981:Xenopus; D029867:Xenopus Proteins; D044844:beta-Transducin Repeat-Containing Proteins
C471646:BTRC protein, Xenopus; C471644:BTRC protein, human; D018797:Cell Cycle Proteins; C503698:CycB protein, Drosophila; D019925:Cyclin A; D019926:Cyclin B; D029721:Drosophila Proteins; D044783:F-Box Proteins; C429107:FBXO5 protein, Xenopus; C498960:FBXO5 protein, human; D029867:Xenopus Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; D016203:CDC2 Protein Kinase; D019204:GTP-Binding Proteins; D010453:Peptide Synthases; D015739:Nocodazole