Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function.

Published

Journal Article

Cell growth and differentiation are controlled by growth factor receptors coupled to the GTPase Ras. Oncogenic mutations disrupt GTPase activity, leading to persistent Ras signaling and cancer progression. Recent evidence indicates that monoubiquitination of Ras leads to Ras activation. Mutation of the primary site of monoubiquitination impairs the ability of activated K-Ras (one of the three mammalian isoforms of Ras) to promote tumor growth. To determine the mechanism of human Ras activation, we chemically ubiquitinated the protein and analyzed its function by NMR, computational modeling and biochemical activity measurements. We established that monoubiquitination has little effect on the binding of Ras to guanine nucleotide, GTP hydrolysis or exchange-factor activation but severely abrogates the response to GTPase-activating proteins in a site-specific manner. These findings reveal a new mechanism by which Ras can trigger persistent signaling in the absence of receptor activation or an oncogenic mutation.

Full Text

Duke Authors

Cited Authors

  • Baker, R; Lewis, SM; Sasaki, AT; Wilkerson, EM; Locasale, JW; Cantley, LC; Kuhlman, B; Dohlman, HG; Campbell, SL

Published Date

  • January 2013

Published In

Volume / Issue

  • 20 / 1

Start / End Page

  • 46 - 52

PubMed ID

  • 23178454

Pubmed Central ID

  • 23178454

Electronic International Standard Serial Number (EISSN)

  • 1545-9985

International Standard Serial Number (ISSN)

  • 1545-9993

Digital Object Identifier (DOI)

  • 10.1038/nsmb.2430

Language

  • eng