Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function.
Nat Struct Mol Biol
; 20(1): 46-52, 2013 Jan.
Article
in En
| MEDLINE
| ID: mdl-23178454
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ras Proteins
/
Ras GTPase-Activating Proteins
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Nat Struct Mol Biol
Journal subject:
BIOLOGIA MOLECULAR
Year:
2013
Document type:
Article
Affiliation country:
Estados Unidos