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Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates
Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates
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Length:
20 minutes
Released:
Nov 23, 2022
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.22.517009v1?rss=1
Authors: Zhang, J. Z., Nguyen, W. H., Rose, J. C., Ong, S.-E., Maly, D. J., Baker, D.
Abstract:
While Ras is known to dynamically shuttle around the cell, the activity, mechanism of activation, and function of non-plasma membrane-localized Ras is unclear due to lack of suitable tools. To address these questions, we used the Latching Orthogonal Cage-Key pRotein (LOCKR) switch platform to generate first-in-class intracellular sensors for endogenous Ras activity (Ras-LOCKR-S) and signaling-dependent proximity labelers (Ras-LOCKR-PL). Localizing these tools to endomembranes and oncogenic condensates, we detected local Ras activity and identified upstream Ras effectors (guanine exchange factors and SAM68) responsible for signaling in these locations. We found further that Major Vault Protein drives RasG12C inhibitor resistance by enhancing signaling at the golgi and altering mitochondrial metabolism during prolonged drug treatment. Together, these results highlight the importance of non-plasma membrane Ras signaling (endomembranes and condensates), and our new sensors should accelerate the discovery of new therapeutic targets.
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Podcast created by Paper Player, LLC
http://biorxiv.org/cgi/content/short/2022.11.22.517009v1?rss=1
Authors: Zhang, J. Z., Nguyen, W. H., Rose, J. C., Ong, S.-E., Maly, D. J., Baker, D.
Abstract:
While Ras is known to dynamically shuttle around the cell, the activity, mechanism of activation, and function of non-plasma membrane-localized Ras is unclear due to lack of suitable tools. To address these questions, we used the Latching Orthogonal Cage-Key pRotein (LOCKR) switch platform to generate first-in-class intracellular sensors for endogenous Ras activity (Ras-LOCKR-S) and signaling-dependent proximity labelers (Ras-LOCKR-PL). Localizing these tools to endomembranes and oncogenic condensates, we detected local Ras activity and identified upstream Ras effectors (guanine exchange factors and SAM68) responsible for signaling in these locations. We found further that Major Vault Protein drives RasG12C inhibitor resistance by enhancing signaling at the golgi and altering mitochondrial metabolism during prolonged drug treatment. Together, these results highlight the importance of non-plasma membrane Ras signaling (endomembranes and condensates), and our new sensors should accelerate the discovery of new therapeutic targets.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Nov 23, 2022
Format:
Podcast episode
Titles in the series (100)
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