期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 20, 期 1, 页码 46-U62出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2430
关键词
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资金
- US National Institutes of Health (NIH) [R01CA089614, R01GM073180-06S1, R01GM073960, R01GM073151, R01GM41890, P01CA117969]
- Program in Molecular and Cellular Biophysics at UNC-CH
- NIH [T32GM008570]
- Japanese Society for the Promotion of Science
- Kanae Foundation for Research Abroad
- Genentech fellowship
Cell growth and differentiation are controlled by growth factor receptors coupled to the GTPase Ras. Oncogenic mutations disrupt GTPase activity, leading to persistent Ras signaling and cancer progression. Recent evidence indicates that monoubiquitination of Ras leads to Ras activation. Mutation of the primary site of monoubiquitination impairs the ability of activated K-Ras (one of the three mammalian isoforms of Ras) to promote tumor growth. To determine the mechanism of human Ras activation, we chemically ubiquitinated the protein and analyzed its function by NMR, computational modeling and biochemical activity measurements. We established that monoubiquitination has little effect on the binding of Ras to guanine nucleotide, GTP hydrolysis or exchange-factor activation but severely abrogates the response to GTPase-activating proteins in a site-specific manner. These findings reveal a new mechanism by which Ras can trigger persistent signaling in the absence of receptor activation or an oncogenic mutation.
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