ArticlePloS one2012
A new dimension to Ras function: a novel role for nucleotide-free Ras in Class II phosphatidylinositol 3-kinase beta (PI3KC2β) regulation.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed.
- Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants.Cell reports · 2022Article
- Inhibition of RAS: proven and potential vulnerabilities.Biochemical Society transactions · 2020Review
- Article
- Covalent Targeting of Ras G12C by Rationally Designed Peptidomimetics.ACS chemical biology · 2020Article
- Therapeutic targeting of RAS: New hope for drugging the "undruggable".Biochimica et biophysica acta. Molecular cell research · 2020Review
- Biology, pathology, and therapeutic targeting of RAS.Advances in cancer research · 2020Review
- Exploiting RAS Nucleotide Cycling as a Strategy for Drugging RAS-Driven Cancers.International journal of molecular sciences · 2019Review
- Direct inhibition of RAS: Quest for the Holy Grail?Seminars in cancer biology · 2019Review
- Personal Mutanomes Meet Modern Oncology Drug Discovery and Precision Health.Pharmacological reviews · 2019Review
- Intersectin scaffold proteins and their role in cell signaling and endocytosis.Biochimica et biophysica acta. Molecular cell research · 2017Review
- Inhibition of RAS function through targeting an allosteric regulatory site.Nature chemical biology · 2017Article
- Downregulation of P-gp, Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell lines.Molecular medicine reports · 2015Article
- Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis.Cancer letters · 2015Article
- The efficacy of Raf kinase recruitment to the GTPase H-ras depends on H-ras membrane conformer-specific nanoclustering.The Journal of biological chemistry · 2014Article
- Druggable orthosteric and allosteric hot spots to target protein-protein interactions.Current pharmaceutical design · 2014Review
- Emerging roles for intersectin (ITSN) in regulating signaling and disease pathways.International journal of molecular sciences · 2013Review
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The intersectin 1 (ITSN1) scaffold stimulates Ras activation on endocytic vesicles without activating classic Ras effectors. The identification of Class II phosphatidylinositol 3-kinase beta, PI3KC2β, as an ITSN1 target on vesicles and the presence of a Ras binding domain (RBD) in PI3KC2β suggests a role for Ras in PI3KC2β activation. Here, we demonstrate that nucleotide-free Ras negatively regulates PI3KC2β activity. PI3KC2β preferentially interacts in vivo with dominant-negative (DN) Ras, which possesses a low affinity for nucleotides. PI3KC2β interaction with DN Ras is disrupted by switch 1 domain mutations in Ras as well as RBD mutations in PI3KC2β. Using purified proteins, we demonstrate that the PI3KC2β-RBD directly binds nucleotide-free Ras in vitro and that this interaction is not disrupted by nucleotide addition. Finally, nucleotide-free Ras but not GTP-loaded Ras inhibits PI3KC2β lipid kinase activity in vitro. Our findings indicate that PI3KC2β interacts with and is regulated by nucleotide-free Ras. These data suggest a novel role for nucleotide-free Ras in cell signaling in which PI3KC2β stabilizes nucleotide-free Ras and that interaction of Ras and PI3KC2β mutually inhibit one another.
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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.