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

Published

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.

Full Text

Duke Authors

Cited Authors

  • Sasaki, AT; Carracedo, A; Locasale, JW; Anastasiou, D; Takeuchi, K; Kahoud, ER; Haviv, S; Asara, JM; Pandolfi, PP; Cantley, LC

Published Date

  • March 8, 2011

Published In

Volume / Issue

  • 4 / 163

Start / End Page

  • ra13 -

PubMed ID

  • 21386094

Pubmed Central ID

  • 21386094

Electronic International Standard Serial Number (EISSN)

  • 1937-9145

International Standard Serial Number (ISSN)

  • 1945-0877

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2001518

Language

  • eng