Chemical Genetic Analysis of RAS Signaling

NIH RePORTER · NIH · R01 · $41,109 · view on reporter.nih.gov ↗

Abstract

Abstract The GTPase RAS functions as a molecular “on/off” switch, existing both in GDP-bound (inactive) and GTP- bound forms (active). Despite functioning as a simple binary switch, RAS is capable of directing complex and diverse cellular processes, including proliferation, migration, survival, and T-cell development. Recent work suggests that the ability of RAS to play complex, often conflicting roles in diverse processes results from differences in cellular context and and/or subcellular localization of its signaling. We have developed a novel chemical genetic tool–called Chemically-Inducible Activator of RAS (CIAR)–to study the dynamics of the signaling networks that are mediated by RAS activity. CIAR allows rapid and dose-dependent activation of RAS signaling with a cell permeable small molecule. With CIAR, we propose to use targeted, quantitative phosphoproteomics and transcriptomics to study the fundamental dynamic behavior of RAS-driven signaling. Subcellularly-localized versions of CIAR will be used to determine the effects of localized RAS activation on the dynamics of RAS-mediated signaling. We will also delineate the interplay between WT RAS and oncogenic RAS signaling and the contribution of WT RAS-mediated signaling to direct inhibitors of oncogenic RAS mutants. Finally, we will develop and use a chemically-controlled toolset for the rapid activation of signaling enzyme oligomers, which will be used to dissect the role that oligomerization state plays in RAS signaling dynamics.

Key facts

NIH application ID
10642578
Project number
3R01GM145011-01A1S1
Recipient
UNIVERSITY OF WASHINGTON
Principal Investigator
Dustin J Maly
Activity code
R01
Funding institute
NIH
Fiscal year
2022
Award amount
$41,109
Award type
3
Project period
2022-04-01 → 2026-02-28