Journal
SCIENCE SIGNALING
Volume 4, Issue 163, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2001518
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Funding
- NCI NIH HHS [P01 CA089021, 1P01CA120964-01A1, P01CA089021, P30 CA006516, P01 CA117969, P01 CA120964, 5P01CA117969, 5P30CA006516-43] Funding Source: Medline
- NIGMS NIH HHS [R01 GM041890, R37 GM041890, R01-GM41890, R01 GM056203] Funding Source: Medline
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The guanosine triphosphate (GTP)-loaded form of the guanosine triphosphatase (GTPase) Ras initiates multiple signaling pathways by binding to various effectors, such as the kinase Raf and phosphatidylinositol 3-kinase (PI3K). Ras activity is increased by guanine nucleotide exchange factors that stimulate guanosine diphosphate release and GTP loading and is inhibited by GTPase-activating proteins that stimulate GTP hydrolysis. KRAS is the most frequently mutated RAS gene in cancer. Here, we report that monoubiquitination of lysine-147 in the guanine nucleotide-binding motif of wild-type K-Ras could lead to enhanced GTP loading. Furthermore, ubiquitination increased the binding of the oncogenic Gly12Val mutant of K-Ras to the downstream effectors PI3K and Raf. Thus, monoubiquitination could enhance GTP loading on K-Ras and increase its affinity for specific downstream effectors, providing a previously unidentified mechanism for Ras activation. Downloaded from stke. sciencemag. org on March 8, 2011
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