Activation of K-RAS by co-mutation of codons 19 and 20 is transforming
1 Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK
2 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
3 Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK, CB2 0QQ, UK
Journal of Molecular Signaling 2011, 6:2 doi:10.1186/1750-2187-6-2Published: 3 March 2011
The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant.