Mechanisms of growth-dependent regulation of the Gin4 kinase

Abstract

Cell-cycle progression is dependent upon cell growth. Cells must therefore translate growth into a proportional signal that indicates when there has been sufficient growth for cell-cycle progression. In budding yeast, the protein kinase Gin4 is required for normal control of bud growth and undergoes gradual multisite hyperphosphorylation and activation that are dependent upon bud growth and correlated with the extent of growth. Together, these observations suggest that Gin4 functions in mechanisms that measure cell growth. Here, we searched for signals that link Gin4 hyperphosphorylation to cell growth. We found that Elm1, a yeast homologue of mammalian Lkb1 kinases, is sufficient in vitro to induce full hyperphosphorylation of Gin4, and likely works by stimulating extensive autophosphorylation of Gin4. We further discovered that casein kinase Iγ, encoded by the YCK1 and YCK2 genes, is required for growth-dependent phosphorylation of Gin4. Yck1/2 are delivered to the growing plasma membrane by post-Golgi vesicles that drive membrane growth, and they are required for normal control of growth. The data suggest that delivery of Yck1/2 to the plasma membrane could play an important role in generating a growth-dependent signal that provides a measure of bud growth.