Tissue-specific oncogenic activity of K-Ras(A146T)
| Autor: | Christian W. Johnson, Pedro A. Perez-Mancera, Steven P. Gygi, Joshua Cook, Benjamin S. Braun, Jessica J. Gierut, Samantha Dale Strasser, Douglas K. Brubaker, Jonathan A. Nowak, Brian A. Joughin, Rebecca A. Destefanis, Kenneth D. Westover, John R. Engen, Lana Bogdanova, Kevin M. Haigis, Carolina Morales, Emily J. Poulin, Jia Lu, Yi Jang Lin, Phaedra C. Ghazi, Asim K. Bera, Joao A. Paulo, Yina Li, Thomas E. Wales, Wei Yan, Sudershan R. Gondi, Roxana E. Iacob, Tannie Q. Huang, Douglas A. Lauffenburger |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Proteomics 0301 basic medicine Proteome Protein Conformation Carcinogenesis Mutant Biology medicine.disease_cause Article Proto-Oncogene Proteins p21(ras) Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Neoplasms medicine Humans Allele Alleles Genetics Mutation Oncogene Oncogenes Phenotype digestive system diseases Cell Transformation Neoplastic 030104 developmental biology Oncology Structural biology Organ Specificity Protein body 030220 oncology & carcinogenesis KRAS Colorectal Neoplasms Signal Transduction |
| Zdroj: | Cancer Discov CANCER DISCOVERY PMC |
| Popis: | 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 KRASG12D, a common mutant form, and KRASA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T 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 KRASG12D and KRASA146T 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 KRAS mutants drive the KRAS mutational pattern seen in cancer. SIGNIFICANCE: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties. National Institutes of Health (Grant U01CA215798) |
| Databáze: | OpenAIRE |
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