Mcs 4 Mitotic Catastrophe Suppressor Regulates the Fission Yeast Cell Cycle through the Wikl - Wisl - Spcl Kinase Cascade

Spcl in Schizosaccharomyces pombe is a member of the stress-activated protein kinase family, an evolutionary conserved subfamily of mitogen-activated protein kinases (MAPKs). Spcl is activated by a MAPK kinase homologue, Wisl, and negatively regulated by Pypl and Pyp2 tyrosine phosphatases. Mutations in the spcl ± and wisl genes cause a G2 cell cycle delay that is exacerbated during stress. Herein, we describe two upstream regulators of the Wisl-Spcl cascade. wikl + (Wisl kinase) was identified from its homology to budding yeast SSK2, which encodes a MAPKK kinase that regulates the HOG1 osmosensing pathway. Awikl cells are impaired in stress-induced activation of Spcl and show a G2 cell cycle delay and osmosensitive growth. Moreover, overproduction of a constitutively active form of Wikl induces hyperactivation of Spcl in a wisl +dependent manner, suggesting that Wikl regulates Spcl through activation of Wisl. A mutation of mcs4' (mitotic catastrophe suppressor) was originally isolated as a suppressor of the mitotic catastrophe phenotype of a cdc2-3w weel-50 double mutant. We have found that mcs4cells are defective at activation of Spcl in response to various forms of stress. Epistasis analysis has placed Mcs4 upstream of Wikl in the Spcl activation cascade. These results indicate that Mcs4 is part of a sensor system for multiple environmental signals that modulates the timing of entry into mitosis by regulating the Wikl-Wisl-Spcl kinase cascade. Inactivation of the sensor system delays the onset of mitosis and rescues lethal premature mitosis in cdc2-3w weel-50 cells.