Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 22, Pages 12121-12130Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2000848117
Keywords
KRAS; NRAS; HRAS; protein-protein interaction; split-luciferase complementation
Categories
Funding
- Cancer Center Core Grant [CA014195]
- Susan G. Komen Foundation [SAC110036]
- NIH/National Cancer Institute [R35 CA197687]
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- Freeberg Foundation
- Genentech
- Sorrento Biosciences
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HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase familymembers using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS-RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome-lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.
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