Negative regulation of APC/C activation by MAPK-mediated attenuation of Cdc20 ^Slp1 under stress

Mitotic anaphase onset is a key cellular process tightly regulated by multiple kinases. The involvement of mitogen-activated protein kinases (MAPKs) in this process has been established in Xenopus egg extracts. However, the detailed regulatory cascade remains elusive, and also it is unknown whether the MAPKs-dependent mitotic regulation is evolutionarily conserved in the single cell eukaryotic organism such as fission yeast ( Schizosaccharomyces pombe ). Here we show that two MAPKs in S. pombe indeed act in concert to restrain anaphase-promoting complex/cyclosome (APC/C) activity upon activation of the spindle assembly checkpoint (SAC). One MAPK, Pmk1, binds and phosphorylates Slp1 ^Cdc20 , the co-activator of APC/C. Phosphorylation of Slp1 ^Cdc20 by Pmk1, but not by Cdk1, promotes its subsequent ubiquitylation and degradation. Intriguingly, Pmk1-mediated phosphorylation event is also required to sustain SAC under environmental stress. Thus, our study establishes a new underlying molecular mechanism of negative regulation of APC/C by MAPK upon stress stimuli, and provides an unappreciated framework for regulation of anaphase entry in eukaryotic cells.