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Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists

Oncogene volume 18, pages 5221–5231 (1999)Cite this article

Abstract

Mutations in the genes encoding for Met, Ret and Kit receptor tyrosine kinases invariably result in increased kinase activity and in the acquisition of transforming potential. However, the requirement of receptor ligands for the transformation process is still unclear. We have investigated the role of hepatocyte growth factor (HGF), the high-affinity ligand for Met, in mutant Met-mediated cell transformation. We provide evidence that the transforming potential displayed by mutant forms of Met found in human cancer is not only sensitive but entirely dependent on the presence of HGF, by showing that mutant Met transforms NIH3T3 fibroblasts, which produce endogenous HGF, but is not able to transform epithelial cells, unless exogenous HGF is supplied. Accordingly, mutant Met-induced transformation of NIH3T3 cells can be inhibited by HGF antagonists and increased by HGF stimulation. We also show that an engineered Met receptor which contains an oncogenic mutation but is impaired in its ability to bind HGF completely loses its transforming activity, which can be rescued by causing receptor dimerization using a monoclonal antibody. These results indicate that point mutations resulting in Met kinase activation are necessary but not sufficient to cause cell transformation, the latter being dependent on ligand-induced receptor dimerization. They also suggest that mutant Met-driven tumour growth depends on the availability and tissue distribution of active HGF, and provide proof-of-concept for the treatment of mutant-Met related pathologies by HGF-antagonizing drugs.

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Acknowledgements

We are grateful to Dr T Miki for the pCEV29.1 plasmid and Dr M Prat for the DO24 antibody. The skilled technical assistance of Mrs R Albano, Mrs L Palmas and Mrs G Petruccelli is gratefully acknowledged. This work has been supported in part by Associazione Italiana per la Ricerca sul Cancro (AIRC), The Giovanni Armenise-Harvard Foundation for Advanced Scientific Research, European Commission (EC) grant no. BMH4-CT98-3852 and MURST-CNR Biotechnology Programme Grant No. 98.00073.PF31 (to PM Comoglio). C Basilico is a Gigi Ghirotti Foundation Fellow and S Pennacchietti is a recipient of an AIRC fellowship.

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  1. Department of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Strada Provinciale 142, Km 3.95, Candiolo (Torino), I-10060, Italy

    Paolo Michieli, Cristina Basilico, Selma Pennacchietti, Antonella Maffè, Luca Tamagnone, Silvia Giordano, Alberto Bardelli & Paolo M Comoglio

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  1. Paolo Michieli
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Michieli, P., Basilico, C., Pennacchietti, S. et al. Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists. Oncogene 18, 5221–5231 (1999). https://doi.org/10.1038/sj.onc.1202899

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