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Computationally designed sensors for endogenous Ras activity reveal signaling effectors within oncogenic granules
Open accessPreprint — published as 10.1038/s41587-023-02107-w · Paper page
Abstract
Genetically encoded biosensors have accelerated biological discovery, however many important targets such as active Ras (Ras-GTP) are difficult to sense as strategies to match a sensor’s sensitivity to the physiological range of target are lacking. Here, we use computational protein design to generate and optimize intracellular sensors of Ras activity ( LOCKR -based S ensor for Ras activity: Ras-LOCKR-S) and proximity labelers of the signaling environment of Ras ( LOCKR -based, Ras activity-dependent P roximity L abeler: Ras-LOCKR-PL). We demonstrate that our tools can measure endogenous Ras activity and environment at subcellular resolution. We illustrate the application of these tools by using them to identify Ras effectors, notably Src-Associated in Mitosis 68 kDa protein (SAM68), enriched in oncogenic EML4-Alk granules. Localizing these sensors to these granules revealed that SAM68 enhances Ras activity specifically at the granules, and SAM68 inhibition sensitizes EML4-Alk-driven cancer cells to existing drug therapies, suggesting a possible therapeutic strategy.
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Metadata
- Authors
- Zhang, J. Z., Nguyen, W. H., Greenwood, N., Rose, J. C., Ong, S.-E., Maly, D. J., & Baker, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Stanford Medicine (US)
- Corresponding author
- Zhang, Jason Z.
- Maly, Dustin J.
- Baker, David
- ORCID
- Venue
- Nature Biotechnology
- Publisher
- openRxiv
- Published
- 2022-11-23
- Volume
- 42
- Issue
- 12
- Pages
- 1888-1898
- ISSN
- 0733-222X (ISSN-L)
- PMC
- PMC11631767
- OpenAlex
- W4391223677
- Cited by
- 37
- References
- 2
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 4 · 2023: 1
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Biotechnology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Health and Human Services (R01GM086858, S10OD021502, R01GM145011)
- Helen Hay Whitney Foundation
- National Institutes of Health (1s10od021502-01a1)
- National Institute of General Medical Sciences (R01GM129090, R01GM145011, R01GM086858)
- Audacious Project
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Keywords
- genetically encoded biosensors, computational protein design, proximity labeling, subcellular localization, Sam68, oncogenic signaling, cancer cell lines
- MeSH terms
- Humans, Biosensing Techniques, Signal Transduction, ras Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing
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