期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 1, 页码 119-126出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2244
关键词
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资金
- US National Institutes of Health (NIH) [R01GM086858, R01CA126792, F30CA189793]
- National Science Foundation CAREER award [CHE-0954242]
- US Department of Defense Breast Cancer Research Program (BCRP) [W81XWH-11-1-0130]
- Howard Hughes Medical Institute
Synthetic protein switches controlled with user-defined inputs are powerful tools for studying and controlling dynamic cellular processes. To date, these approaches have relied primarily on intermolecular regulation. Here we report a computationally guided framework for engineering intramolecular regulation of protein function. We utilize this framework to develop chemically inducible activator of RAS (CIAR), a single-component RAS rheostat that directly activates endogenous RAS in response to a small molecule. Using CIAR, we show that direct RAS activation elicits markedly different RAS-ERK signaling dynamics from growth factor stimulation, and that these dynamics differ among cell types. We also found that the clinically approved RAF inhibitor vemurafenib potently primes cells to respond to direct wild-type RAS activation. These results demonstrate the utility of CIAR for quantitatively interrogating RAS signaling. Finally, we demonstrate the general utility of our approach in design of intramolecularly regulated protein tools by applying it to the Rho family of guanine nucleotide exchange factors.
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