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Vol. 11, Issue 5, 1555-1569, May 2000
and
*Research Institute of Molecular Pathology, A-1030 Vienna,
Austria; and The ordered activation of the ubiquitin protein ligase
anaphase-promoting complex (APC) or cyclosome by CDC20 in
metaphase and by CDH1 in telophase is essential for anaphase and
for exit from mitosis, respectively. Here, we show that CDC20 can only bind to and activate the mitotically phosphorylated form of the Xenopus and the human APC in vitro. In contrast, the
analysis of phosphorylated and nonphosphorylated forms of CDC20
suggests that CDC20 phosphorylation is neither sufficient nor required for APC activation. On the basis of these results and the observation that APC phosphorylation correlates with APC activation in vivo, we
propose that mitotic APC phosphorylation is an important mechanism that
controls the proper timing of APCCDC20 activation. We
further show that CDH1 is phosphorylated in vivo during S, G2, and M
phase and that CDH1 levels fluctuate during the cell cycle. In vitro,
phosphorylated CDH1 neither binds to nor activates the APC as
efficiently as does nonphosphorylated CDH1. Nonphosphorylatable CDH1
mutants constitutively activate APC in vitro and in vivo, whereas
mutants mimicking the phosphorylated form of CDH1 are constitutively
inactive. These results suggest that mitotic kinases have antagonistic
roles in regulating APCCDC20 and APCCDH1; the
phosphorylation of APC subunits is required to allow APC activation by
CDC20, whereas the phosphorylation of CDH1 prevents activation of the
APC by CDH1. These mechanisms can explain the temporal order of APC
activation by CDC20 and CDH1 and may help to ensure that exit from
mitosis is not initiated before anaphase has occurred.
Protein Interaction Laboratory, Odense
University, DK-5230 Odense M, Denmark
Corresponding author. E-mail
address: peters{at}nt.imp.univie.ac.at.
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