Nim1-related kinases coordinate cell cycle progression with the organization of the peripheral cytoskeleton in yeast

The mechanisms that couple cell cycle progression with the organization of the peripheral cytoskeleton are poorly understood. In Saccharomyces cerevis iae, the Swe1 protein has been shown previously to phosphorylate and inacti vate the cyclin-dependent kinase, Cdc28, thereby delaying the onset of mito sis. The nim1-related protein kinase, Hsl1, induces entry into mitosis by n egatively regulating Swe1. We have found that Hsl1 physically associates wi th the septin cytoskeleton in vivo and that Hsl1 kinase activity depends on proper septin function. Genetic analysis indicates that two additional Hsl 1-related kinases, Kcc4 and Gin4, act redundantly with Hsl1 to regulate Swe 1. Kcc4, like Hsl1 and Gin4, was found to localize to the bud neck in a sep tin-dependent fashion. Interestingly, hsl1 kcc4 gin4 triple mutants develop a cellular morphology extremely similar to that of septin mutants. Consist ent with the idea that Hsl1, Kcc4, and Gin4 link entry into mitosis to prop er septin organization, we find that septin mutants incubated at the restri ctive temperature trigger a Swe1-dependent mitotic delay that is necessary to maintain cell viability. These results reveal for the first time how cel ls monitor the organization of their cytoskeleton and demonstrate the exist ence of a cell cycle checkpoint that responds to defects in the peripheral cytoskeleton. Moreover, Hsl1, Kcc4, and Gin4 have homologs in higher eukary otes, suggesting that the regulation of Swe1/Wee1 by this class of kinases is highly conserved.