title: Transbilayer phospholipid flipping regulates Cdc42p signaling during polarized cell growth via Rga GTPase-activating proteins.
abstract: An important problem in polarized morphogenesis is how polarized transport of membrane vesicles is spatiotemporally regulated. Here, we report that a local change in the transbilayer phospholipid distribution of the plasma membrane regulates the axis of polarized growth. Type 4 P-type ATPases Lem3p-Dnf1p and -Dnf2p are putative heteromeric phospholipid flippases in budding yeast that are localized to polarized sites on the plasma membrane. The lem3Delta mutant exhibits prolonged apical growth due to a defect in the switch to isotropic bud growth. In lem3Delta cells, the small GTPase Cdc42p remains polarized at the bud tip where phosphatidylethanolamine remains exposed on the outer leaflet. Intriguingly, phosphatidylethanolamine and phosphatidylserine stimulate GTPase-activating protein (GAP) activity of Rga1p and Rga2p toward Cdc42p, whereas PI(4,5)P(2) inhibits it. We propose that a redistribution of phospholipids to the inner leaflet of the plasma membrane triggers the dispersal of Cdc42p from the apical growth site, through activation of GAPs.
authors.affiliation: Division of Molecular Interaction, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Saito
authors.affiliation: Division of Molecular Interaction, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Konomi
authors.initials: K
authors.lastname: Fujimura-Kamada
authors.affiliation: Division of Molecular Interaction, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Hanamatsu
authors.affiliation: Division of Molecular Biology and Information, Institute for Chemical Science, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Kato
authors.affiliation: Division of Molecular Biology and Information, Institute for Chemical Science, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Umeda
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22904, USA; Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA.
authors.forename: Keith G
authors.initials: KG
authors.lastname: Kozminski
authors.affiliation: Division of Molecular Interaction, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan. Electronic address: k-tanaka@igm.hokudai.ac.jp.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D049109:Cell Proliferation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D009154:Mutation; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism / Q000502:physiology*; D020846:cdc42 GTP-Binding Protein, Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; C478771:Lem3 protein, S cerevisiae; D026901:Membrane Transport Proteins; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D010743:Phospholipids; C526447:Rga1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C483858:phosphatidylethanolamine; D000251:Adenosine Triphosphatases; C480602:Dnf2 protein, S cerevisiae; D019205:GTP-Binding Protein alpha Subunits, Gs; D020846:cdc42 GTP-Binding Protein, Saccharomyces cerevisiae; C480601:Dnf1 protein, S cerevisiae