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Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET

Oncogene volume 18, pages 4275–4281 (1999)Cite this article

Abstract

TPR-MET, a transforming counterpart of the c-MET proto-oncogene detected in experimental and human cancer, results from fusion of the MET kinase domain with a dimerization motif encoded by TPR. In this rearrangement the exons encoding the Met extracellular, transmembrane and juxtamembrane domains are lost. The juxtamembrane domain has been suggested to be a regulatory region endowed with negative feedback control. To understand whether its absence is critical for the generation of the Tpr-Met transforming potential, we produced a chimeric molecule (Tpr-juxtaMet) with a conserved juxtamembrane domain. The presence of the domain (aa 962–1009) strongly inhibited Tpr-Met dependent cell transformation. Cell proliferation, anchorage-independent growth, motility and invasion were also impaired. The enzymatic behavior of Tpr-Met and Tpr-juxtaMet was the same, while Tpr-juxtaMet ability to associate cytoplasmic signal transducers and to elicit downstream signaling was severely impaired. These data indicate that the presence of the juxtamembrane domain counterbalances the Tpr-Met transforming potential and therefore the loss of the exon encoding the juxtamembrane domain is crucial in the generation of the active TPR-MET oncogene.

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Acknowledgements

We wish to thank Dr Toru Miki for the pCEV29.1 plasmid, E Wright and A Cignetto for editing the manuscript, Stefano Fracchioli for his enthusiastic help in performing the biological experiments and P Michieli for helpful suggestions in performing focus forming assays. M Prat and P Maggiora are gratefully acknowledged for revising the manuscript. R Albano is acknowledged for providing DQ13 Mab and G Petruccelli for technical assistance. This work was supported by research grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and from the Giovanni Armenise-Harvard Foundation for Advanced Scientific Research.

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  1. Institute for Cancer Research and Treatment (IRCC), University of Torino School of Medicine, Str. Prov. 142, Km. 3.95, Torino, 10060, Candiolo, Italy

    Elisa Vigna, Daniela Gramaglia, Paola Longati, Alberto Bardelli & Paolo M Comoglio

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  1. Elisa Vigna
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  2. Daniela Gramaglia
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  3. Paola Longati
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  4. Alberto Bardelli
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  5. Paolo M Comoglio
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Vigna, E., Gramaglia, D., Longati, P. et al. Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET. Oncogene 18, 4275–4281 (1999). https://doi.org/10.1038/sj.onc.1202791

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