Tissue-Specific Oncogenic Activity of KRAS^A146T.

ABSTRACT: KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRAS^G12D, a common mutant form, and KRAS^A146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRAS^A146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor-induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRAS

SUBMITTER: Poulin EJ 

PROVIDER: S-EPMC6548671 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature