Journal
EMBO JOURNAL
Volume 22, Issue 4, Pages 797-806Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/cdg071
Keywords
anaphase promoting complex-cyclosome; Mad2; metaphase arrest; mitotic checkpoint; phosphorylation
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Funding
- NIGMS NIH HHS [R01 GM54601] Funding Source: Medline
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Improper attachment of the mitotic spindle to the kinetochores of paired sister chromatids in mitosis is monitored by a checkpoint that leads to an arrest in early metaphase. This arrest requires the inhibitory association of Mad2 with the anaphase promoting complex/cyclosome (APC/C). It is not known how the association of Mad2 with the kinetochore and the APC/C is regulated in mitosis. Here, we demonstrate that human Mad2 is modified through phosphorylation on multiple serine residues in vivo in a cell cycle dependent manner and that only unphosphorylated Mad2 interacts with Mad1 or the APC/C in vivo. A Mad2 mutant containing serine to aspartic acid mutations mimicking the C-terminal phosphorylation events fails to interact with Mad1 or the APC/C and acts as a dominant-negative antagonist of wild-type Mad2. These data suggest that the phosphorylation state of Mad2 regulates its checkpoint activity by modulating its association with Mad1 and the APC/C.
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