THE FISSION YEAST MITOTIC REGULATOR WIN1(+) ENCODES AN MAP KINASE KINASE KINASE THAT PHOSPHORYLATES AND ACTIVATES WIS1 MAP KINASE KINASE INRESPONSE TO HIGH OSMOLARITY

The Schizosaccharomyces pombe win1-1 mutant has a defect in the G2-M t ransition of the cell cycle. Although the defect is suppressed by wis1 (+) and wis4(+), which are components of a stress-activated MAP kinase pathway that links stress response and cell cycle control, the molecu lar identity of Win1 has not been known. We show here that win1(+) enc odes a polypeptide of 1436 residues with an apparent molecular size of 180 kDa and demonstrate that Win1 is a MAP kinase kinase kinase that phosphorylates and activates Wis1. Despite extensive similarities betw een Win1 and Wis4, the two MAP kinase kinase kinases have distinct fun ctions. Wis4 is able to compensate for loss of Win1 only under unstres sed conditions to maintain basal Wis1 activity, but it fails to suppre ss the osmo-signaling defect conferred by win1 mutations. The win1-1 m utation is a spontaneous duplication of 16 nucleotides, which leads to a frameshift and production of a truncated protein lacking the kinase domain. We discuss the cell cycle phenotype of the win1-1 cdc25-22 we e1-50 mutant and its suppression by wis genes.