ArticleMolecular and cellular biology2016
AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2.
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 41 papers.
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Who cites it
41 citing papers in PubMed, 66 citations in OpenAlex.
- MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids.The Journal of cell biology · 2025Article
- Drugging Ras trafficking-are there new roads to travel?npj drug discovery · 2025Review
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- An Improved PDE6D Inhibitor Combines with Sildenafil To InhibitJournal of medicinal chemistry · 2024Article
- KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance.Current oncology (Toronto, Ont.) · 2024Review
- A new ferrocene derivative blocks K-Ras localization and function by oxidative modification at His95.Life science alliance · 2023Article
- Origin and Evolution of RAS Membrane Targeting.Oncogene · 2023Article
- RAS nanoclusters are cell surface transducers that convert extracellular stimuli to intracellular signalling.FEBS letters · 2023Review
- Origin and evolution of RAS oncoprotein membrane targeting.Research square · 2023Article
- The Four Homeostasis Knights: In Balance upon Post-Translational Modifications.International journal of molecular sciences · 2022Review
- Prkg2 regulates alveolar type 2-mediated re-alveolarization.Stem cell research & therapy · 2022Article
- Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado.Molecular cancer research : MCR · 2022Article
- Post-translational modification of RAS proteins.Current opinion in structural biology · 2021Review
- Lipid Profiles of RAS Nanoclusters Regulate RAS Function.Biomolecules · 2021Review
- Post-translational modification of KRAS: potential targets for cancer therapy.Acta pharmacologica Sinica · 2021Review
- Osimertinib-resistant NSCLC cells activate ERBB2 and YAP/TAZ and are killed by neratinib.Biochemical pharmacology · 2021Article
- Effects of SGLT2 inhibitors on eGFR in type 2 diabetic patients-the role of antidiabetic and antihypertensive medications.Hypertension research : official journal of the Japanese Society of Hypertension · 2021Article
- Review
- Approaches to inhibiting oncogenic K-Ras.Small GTPases · 2021Review
- Promotion of cancer cell stemness by Ras.Biochemical Society transactions · 2021Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells, activated PKG2 selectively colocalizes with K-Ras on the plasma membrane and phosphorylates K-Ras at Ser181 in the C-terminal polybasic domain. K-Ras phosphorylation by PKG2 is triggered by activation of AMP-activated protein kinase (AMPK) and requires endothelial nitric oxide synthase and soluble guanylyl cyclase. Phosphorylated K-Ras reorganizes into distinct nanoclusters that retune the signal output. Phosphorylation acutely enhances K-Ras plasma membrane affinity, but phosphorylated K-Ras is progressively lost from the plasma membrane via endocytic recycling. Concordantly, chronic pharmacological activation of AMPK → PKG2 signaling with mitochondrial inhibitors, nitric oxide, or sildenafil inhibits proliferation of K-Ras-positive non-small cell lung cancer cells. The study shows that K-Ras is a target of a metabolic stress-signaling pathway that can be leveraged to inhibit oncogenic K-Ras function.
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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.