title: KRas localizes to the plasma membrane by spatial cycles of solubilization, trapping and vesicular transport.
abstract: KRas is a major proto-oncogene product whose signaling activity depends on its level of enrichment on the plasma membrane (PM). This PM localization relies on posttranslational prenylation for membrane affinity, while PM specificity has been attributed to electrostatic interactions between negatively charged phospholipids in the PM and basic amino-acids in the C terminus of KRas. By measuring kinetic parameters of KRas dynamics in living cells with a cellular-automata-based data-fitting approach in realistic cell-geometries, we show that charge-based specificity is not sufficient to generate PM enrichment in light of the total surface area of endomembranes. Instead, mislocalized KRas is continuously sequestered from endomembranes by cytosolic PDEδ to be unloaded in an Arl2-dependent manner to perinuclear membranes. Electrostatic interactions then trap KRas at the recycling endosome (RE), from where vesicular transport restores enrichment on the PM. This energy driven reaction-diffusion cycle explains how small molecule targeting of PDEδ affects the spatial organization of KRas.
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Schmick
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Nachiket
authors.initials: N
authors.lastname: Vartak
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Papke
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Marija
authors.initials: M
authors.lastname: Kovacevic
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Dina C
authors.initials: DC
authors.lastname: Truxius
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Lisaweta
authors.initials: L
authors.lastname: Rossmannek
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Fakultät Chemie, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44221 Dortmund, Germany. Electronic address: philippe.bastiaens@mpi-dortmund.mpg.de.
authors.forename: Philippe I H
authors.initials: PIH
authors.lastname: Bastiaens
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004285:Dogs; D011992:Endosomes / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D000090063:Proto-Oncogene Mas; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C410130:ARL2 protein, human; D019204:GTP-Binding Proteins; D018631:ras Proteins