KRas Localizes to the Plasma Membrane by Spatial Cycles of Solubilization, Trapping and Vesicular Transport
Open accessAbstract
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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KRAS can only be fully activated by upstream signaling proteins when it is located on the cell membrane.
“KRAS can only be fully activated by upstream signaling proteins when it is located on the cell membrane.335”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [335]
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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
- bronze
- doi.org
- Licence
- 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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