Journal
CELL REPORTS
Volume 29, Issue 11, Pages 3448-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.045
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Funding
- MD Anderson SPOREs in Ovarian Cancer [NCI P50 CA 83639, CA 217685]
- National Cancer Institute [R01 CA135354]
- Cancer Prevention and Research Institute of Texas [RP140429]
- Shared Resources of the MD Anderson CCSG grant [NCI P30 CA16672]
- National Foundation for Cancer Research
- Anne and Henry Zarrow Foundation
- NIH [TL1TR000369, UL1TF000371]
- American Legion Auxiliary
- Ann and Sol Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund Alliance
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Oncogenic RAS mutations drive cancers at many sites. Recent reports suggest that RAS dimerization, multimerization, and clustering correlate strongly with activation of RAS signaling. We have found that re-expression of DIRAS3, a RAS-related small GTPase tumor suppressor that is downregulated in multiple cancers, inhibits RAS/mitogen-activated protein kinase (MAPK) signaling by interacting directly with RAS-forming heteromers, disrupting RAS clustering, inhibiting Raf kinase activation, and inhibiting transformation and growth of cancer cells and xenografts. Disruption of K-RAS cluster formation requires the N terminus of DIRAS3 and interaction of both DIRAS3 and K-RAS with the plasma membrane. Interaction of DIRAS3 with both K-RAS and H-RAS suggests a strategy for inhibiting oncogenic RAS function.
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