Abstract
The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c–Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers1,2,3,4. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver5,6,7,8,9,10,11. Studies of the mechanism of c-Src regulation have suggested that c-Src kinase activity is downregulated by phosphorylation of a critical carboxy-terminal tyrosine (Tyr 530 in human c-Src, equivalent to Tyr 527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region12,13,14,15,16,17,18. We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis. These results provide, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.
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Acknowledgements
We thank D. Agrawal and S. Sebti for helpful discussions; M. Wloch for his assistance in procurement of human tumours; K. Cohn for his contribution of human tumour samples for analysis; C. Newton for tail vein injections; and Moffitt Cancer Center's Molecular Imaging, Pathology, and Molecular Biology core facilities. This work was supported by grants from the National Institutes of Health CA65512 and the American Cancer Society RPG MGO–97551 (T.J.Y.) and CA55652 (R.J.) and by the NCIC/Canadian Breast Cancer Research Initiative and the Medical Research Council of Canada.
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Irby, R., Mao, W., Coppola, D. et al. Activating SRC mutation in a subset of advanced human colon cancers . Nat Genet 21, 187–190 (1999). https://doi.org/10.1038/5971
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DOI: https://doi.org/10.1038/5971
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