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Activating SRC mutation in a subset of advanced human colon cancers

Nature Genetics volume 21, pages 187–190 (1999)Cite this article

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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Figure 1: Identification of SRC 531 mutation in human tumours.
Figure 2: Confirmation of SRC 531 mutation in tumours by mutant allele–specific PCR.
Figure 3: Kinase activity and phosphotyrosine analysis of normal and mutant Src proteins.
Figure 4: Analysis of fibroblasts transfected with the Src 531 expression construct for cellular transformation and metastatic potential.

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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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Authors and Affiliations

  1. Department of Surgery, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, USA

    Rosalyn B. Irby, Weiguang Mao, Jimmy Kang, Jean Marc Loubeau, Richard Karl & Timothy J. Yeatman

  2. Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, USA

    Domenico Coppola, Walter Trudeau & Richard Jove

  3. Department of Biochemistry and Molecular Biology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, USA

    Richard Jove

  4. Department of Medical Biochemistry, University of Calgary Medical Center, T2N4N1, Alberta, Canada

    Donald J. Fujita

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  1. Rosalyn B. Irby
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Correspondence to Timothy J. Yeatman.

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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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