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Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr–Met, involves exclusion from the endocytic degradative pathway

Oncogene volume 26, pages 7213–7221 (2007)Cite this article

Abstract

Multiple mechanisms of dysregulation of receptor tyrosine kinases (RTKs) are observed in human cancers. In addition to gain-of-function, loss of negative regulation also contributes to oncogenic activation of RTKs. Negative regulation of many RTKs involves their internalization and degradation in the lysosome, a process regulated through ubiquitination. RTK oncoproteins activated following chromosomal translocation, are no longer transmembrane proteins, and are predicted to escape lysosomal degradation. To test this, we used the Tpr–Met oncogene, generated following chromosomal translocation of the hepatocyte growth factor receptor (Met). Unlike Met, Tpr–Met is localized in the cytoplasm and also lacks the binding site for Cbl ubiquitin ligases. We determined whether subcellular localization of Tpr–Met, and/or loss of its Cbl-binding site, is important for oncogenic activity. Presence of a Cbl-binding site and ubiquitination of cytosolic Tpr–Met oncoproteins does not alter their transforming activity. In contrast, plasma membrane targeting allows Tpr–Met to enter the endocytic pathway, and Tpr–Met transforming activity as well as protein stability are decreased in a Cbl-dependent manner. We show that transformation by Tpr–Met is in part dependent on its ability to escape normal downregulatory mechanisms. This provides a paradigm for many RTK oncoproteins activated following chromosomal translocation.

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Acknowledgements

We thank Anie Monast for help with the mice and Park Laboratory for helpful comments. This research was supported by grant (MOP-11545) to MP from the Canadian Institutes of Health Research. HM is a recipient of a Canadian Institute Health Research Cancer Consortium award, PP is a recipient of a Terry Fox research studentship from the National Cancer Institute of Canada. MP is a senior scholar of the CIHR. The authors declare that they have no competing financial interests.

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Authors and Affiliations

  1. Molecular Oncology Group, McGill University Health Centre, Montreal, Quebec, Canada

    H H L Mak, P Peschard & M Park

  2. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    H H L Mak, P Peschard & M Park

  3. Department of Medicine, McGill University, Montreal, Quebec, Canada

    T Lin, M A Naujokas, D Zuo & M Park

  4. Department of Oncology, McGill University, Montreal, Quebec, Canada

    M Park

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  1. H H L Mak
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  2. P Peschard
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  6. M Park
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Correspondence to M Park.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Mak, H., Peschard, P., Lin, T. et al. Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr–Met, involves exclusion from the endocytic degradative pathway. Oncogene 26, 7213–7221 (2007). https://doi.org/10.1038/sj.onc.1210522

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