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Computationally designed sensors detect endogenous Ras activity and signaling effectors at subcellular resolution
Jason Z Zhang1,2,3, William H Nguyen4, Nathan Greenwood4,5
1Department of Biochemistry, University of Washington, Seattle, WA, USA. jzz0428@uw.edu.
Nature Biotechnology
|January 25, 2024
Summary
Researchers developed new biosensors to detect Ras protein activity within cells. These tools identified proteins interacting with Ras in cancer cells and revealed a protein that enhances Ras activity, offering insights into cancer and potential therapies.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- Genetically encoded biosensors are crucial for studying signaling protein activity.
- A key limitation has been matching sensor sensitivity to physiological target concentrations.
Purpose of the Study:
- To develop novel biosensors for detecting intracellular Ras activity and its signaling environment.
- To identify Ras-interacting proteins and understand Ras function in specific subcellular locations.
Main Methods:
- Computational protein design was employed to create Ras activity sensors (Ras-LOCKR-S) and proximity labelers (Ras-LOCKR-PL).
- These tools were utilized in human cancer cell lines to detect endogenous Ras activity at subcellular resolution.
Main Results:
- The developed sensors successfully detected endogenous Ras activity and labeled the surrounding signaling environment.
- Oncogenic EML4-Alk granules were found to contain Ras-interacting proteins.
- The Src-Associated in Mitosis 68-kDa (SAM68) protein was identified as a specific enhancer of Ras activity within these granules.
Conclusions:
- The ability to localize Ras activity within subcellular compartments advances the understanding of Ras function in cellular processes.
- These findings may pave the way for novel therapeutic strategies targeting Ras signaling in diseases like cancer.
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