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Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors.

Authors
  • Sasaki, Atsuo T
  • Carracedo, Arkaitz
  • Locasale, Jason W
  • Anastasiou, Dimitrios
  • Takeuchi, Koh
  • Kahoud, Emily Rose
  • Haviv, Sasson
  • Asara, John M
  • Pandolfi, Pier Paolo
  • Cantley, Lewis C
Type
Published Article
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Jan 01, 2011
Volume
4
Issue
163
Identifiers
DOI: 10.1126/scisignal.2001518
PMID: 21386094
Source
Medline
License
Unknown

Abstract

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.

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