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Sci Signal. 2011 Mar 8;4(163):ra13. doi: 10.1126/scisignal.2001518.

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

Author information

1
1Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

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.

PMID:
21386094
PMCID:
PMC3437993
DOI:
10.1126/scisignal.2001518
[Indexed for MEDLINE]
Free PMC Article

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