Cited by 246Cellular transport and secretionProtein Kinase Regulation and GTPase SignalingLipid Membrane Structure and Behavior

KRas Localizes to the Plasma Membrane by Spatial Cycles of Solubilization, Trapping and Vesicular Transport

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Schmick, Malte, Vartak, Nachiket, Papke, Björn, Kovacevic, Marija, Truxius, Dina C., Rossmannek, Lisaweta, Bastiaens, Philippe I.H.·2014·Cell

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.

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Crossref · 10.1016/j.cell.2014.02.051

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Authors
Schmick, M., Vartak, N., Papke, B., Kovacevic, M., Truxius, D. C., Rossmannek, L., & Bastiaens, P. I. H.
Affiliations
  • Max Planck Institute of Molecular Physiology (DE)
  • TU Dortmund University (DE)
Corresponding author
Bastiaens, Philippe I.H.
Venue
Cell
Publisher
Elsevier BV
Published
2014-04
Volume
157
Issue
2
Pages
459-471
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2002036996
Cited by
243
References
37
Citations by year
2026: 9 · 2025: 16 · 2024: 17 · 2023: 16 · 2022: 12 · 2021: 24 · 2020: 29 · 2019: 26 · 2018: 29 · 2017: 27 · 2016: 21 · 2015: 11 · 2014: 5
FWCI
10.63
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Digital Library (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
KRAS, plasma membrane localization, prenylation, PDEδ, ARL2, recycling endosomes, vesicle trafficking, cellular automata, membrane trafficking, small molecule targeting
MeSH terms
Proto-Oncogene Mas, Animals, Cell Membrane, Dogs, Humans, Intracellular Membranes, Endosomes, 3',5'-Cyclic-GMP Phosphodiesterases, ras Proteins, GTP-Binding Proteins, Madin Darby Canine Kidney Cells

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