ArticleMolecular and cellular biology2016
Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane.
Article in Molecular and cellular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 121 citations in OpenAlex.
- KRAS4a and KRAS4b show distinct lipid-dependent regulation of RAS-RAF membrane dynamics.The Journal of biological chemistry · 2026Article
- Monitoring phospholipid dynamics in vivo with a fluorescent dye octadecyl rhodamine B.Cell structure and function · 2025Article
- Article
- Membrane receptors cluster phosphatidylserine to activate LC3-associated phagocytosis.Nature cell biology · 2025Article
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids.The Journal of cell biology · 2025Article
- The Multifaceted Role of Calcium Signaling in Regulated Necrosis.Biomolecules · 2025Review
- From disorder comes function: Regulation of small GTPase function by intrinsically disordered lipidated membrane anchor.Current opinion in structural biology · 2024Review
- TRPV4-dependent CaBiophysical journal · 2024Article
- Evaluation of fendiline treatment in VP40 system with nucleation-elongation process: a computational model of Ebola virus matrix protein assembly.Microbiology spectrum · 2024Article
- Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk.The FEBS journal · 2024Review
- Spontaneous signal generation by an excitable system for cell migration.Frontiers in cell and developmental biology · 2024Review
- Membrane anchoring of the DIRAS3 N-terminal extension permits tumor suppressor function.iScience · 2023Article
- A new look at Hsp70 activity in phosphatidylserine-enriched membranes: chaperone-induced quasi-interdigitated lipid phase.Scientific reports · 2023Article
- A new ferrocene derivative blocks K-Ras localization and function by oxidative modification at His95.Life science alliance · 2023Article
- RAS GTPases and Interleaflet Coupling in the Plasma Membrane.Cold Spring Harbor perspectives in biology · 2023Review
- Sphingomyelin metabolism underlies Ras excitability for efficient cell migration and chemotaxis.Cell structure and function · 2023Article
- The relevance of acid sphingomyelinase as a potential target for therapeutic intervention in hepatic disorders: current scenario and anticipated trends.Archives of toxicology · 2023Review
- RAS nanoclusters are cell surface transducers that convert extracellular stimuli to intracellular signalling.FEBS letters · 2023Review
- Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding.EMBO reports · 2022Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.