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Cancer Discov. 2019 Apr 5. pii: CD-18-1220. doi: 10.1158/2159-8290.CD-18-1220. [Epub ahead of print]

Tissue-specific oncogenic activity of K-RasA146T.

Author information

1
Medicine, Beth Israel Deaconess Medical Centerl.
2
The University of Texas Southwestern Medical Center.
3
Radiation Oncology, The University of Texas Southwestern Medical Center.
4
Beth Israel Deaconess Medical Center.
5
Massachusetts Institute of Technology.
6
Cell Biology, Harvard Medical School.
7
UCSF.
8
biochemistry, The University of Texas Southwestern Medical Center.
9
Department of Medicine, Beth Israel Deaconess Medical Center.
10
Department of Pathology, Brigham and Women's Hospital.
11
Biological Engineering, Massachusetts Institute of Technology.
12
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology.
13
Division of Hematology and Oncology, University of Wisconsin-Madison.
14
Medicine- Genetics, Beth Israel Deaconess Medical Center.
15
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas.
16
Northeastern University.
17
Biochemistry and Molecular Genetics, University of Illinois at Chicago.
18
Chemistry & Chemical Biology, Northeastern University.
19
Molecular & Clinical Cancer Medicine, University of Liverpool.
20
Pediatric Hematology/Oncology, University of California, San Francisco.
21
Harvard Medical School.
22
Department of Biological Engineering, Massachusetts Institute of Technology.
23
Cancer Research Institute, Beth Israel Deaconess Medical Center khaigis@bidmc.harvard.edu.

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 K-Ras proteins. We used a cross-disciplinary approach to compare K-RasG12D, a common mutant form, and K-RasA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that K-RasA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates K-Ras by promoting a high rate of intrinsic and GEF-induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that K-RasG12D and K-RasA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different K-Ras mutants drive the KRAS mutational pattern seen in cancer.

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