A dual mechanism of APC/C inhibition by MAP kinases

Abstract

Mitotic anaphase onset is a key cellular process that is tightly regulated by multiple kinases. The involvement of mitogen-activated protein kinases (MAPKs) in this process has been established long ago in Xenopus egg extracts. However, despite its importance, it is still unclear which MAPK(s) is actually involved, this impedes the further understanding of the regulatory cascade. In this study, we first demonstrated that the involvement of MAPKs in mitotic anaphase onset regulation is evolutionarily conserved in the fission yeast (Schizosaccharomyces pombe). Then, we found that two of the three fission yeast MAPK signaling pathways act in concert to restrain anaphase-promoting complex/cyclosome (APC/C) activity upon activation of the spindle assembly checkpoint (SAC). The first pathway involves the phosphorylation of Mad2, a component of the core mitotic check complex (MCC), by MAPK Sty1, which enhances the tight binding of MCC to APC/C. The second pathway involves MAPK Pmk1 phosphorylation of Slp1Cdc20, the fission yeast homologue of Cdc20 and the co-activator of APC/C, which promotes the degradation of Slp1Cdc20. Both phosphorylation events are required to sustain mitotic arrest in response to spindle defects. These results clarified a detailed regulation cascade of the ubiquitous MAPK signaling in spindle checkpoint activation, APC/C inhibition and anaphase entry, which is vital for accurate chromosome segregation and cell viability.