Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors.
Journal Article (Journal Article)
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.
- Sasaki, AT; Carracedo, A; Locasale, JW; Anastasiou, D; Takeuchi, K; Kahoud, ER; Haviv, S; Asara, JM; Pandolfi, PP; Cantley, LC
- March 8, 2011
Volume / Issue
- 4 / 163
Start / End Page
- ra13 -
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States