Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function Academic Article uri icon

Overview

MeSH Major

  • ras GTPase-Activating Proteins
  • ras Proteins

abstract

  • 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.

publication date

  • January 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3537887

Digital Object Identifier (DOI)

  • 10.1038/nsmb.2430

PubMed ID

  • 23178454

Additional Document Info

start page

  • 46

end page

  • 52

volume

  • 20

number

  • 1