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| Subject Categories: Cell Cycle |
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| The EMBO Journal
(2003) 22, 6598–6609, doi:10.1093/emboj/cdg627 |
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| Mitotic regulation of the human anaphase-promoting complex by phosphorylation |
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| Claudine Kraft1, 3, Franz Herzog1, 3, Christian Gieffers1, Karl Mechtler1, Anja Hagting2, Jonathon Pines2 and Jan-Michael Peters1 |
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1 Research Institute of Molecular Pathology (IMP), Dr Bohr-Gasse 7, 1030 Vienna, Austria 2 Wellcome/Cancer Research Campaign Institute, Tennis Court Road, Cambridge CB2 1QR, UK 3 C.Kraft and F.Herzog contributed equally to this work To whom correspondence should be addressed Jan-Michael Peters, peters@imp.univie.ac.at Received 6 August 2003; Revised 20 August 2003; Accepted 27 October 2003. |
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| Abstract |
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| The anaphase-promoting complex (APC) or cyclosome is a ubiquitin ligase that initiates anaphase and mitotic exit. APC activation is thought to depend on APC phosphorylation and Cdc20 binding. We have identified 43 phospho-sites on APC of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7. In vitro, at least 15 of the mitotic phospho-sites can be generated by cyclin-dependent kinase 1 (Cdk1), and 3 by Polo-like kinase 1 (Plk1). APC phosphorylation by Cdk1, but not by Plk1, is sufficient for increased Cdc20 binding and APC activation. Immunofluorescence microscopy using phospho-antibodies indicates that APC phosphorylation is initiated in prophase during nuclear uptake of cyclin B1. In prometaphase phospho-APC accumulates on centrosomes where cyclin B ubiquitination is initiated, appears throughout the cytosol and disappears during mitotic exit. Plk1 depletion neither prevents APC phosphorylation nor cyclin A destruction in vivo. These observations imply that APC activation is initiated by Cdk1 already in the nuclei of late prophase cells. |
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| Keywords: anaphase-promoting complex, Cdk1, mitosis, phosphorylation, Plk1 |
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