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Cross-talk between the proto-oncogenes Met and Ron

Oncogene volume 19, pages 3041–3049 (2000)Cite this article

Abstract

Scatter Factors control a complex genetic program known as ‘invasive growth’. HGF (Scatter factor 1) and MSP (Scatter Factor 2) bind to tyrosine kinase receptors encoded by the proto-oncogenes MET and RON. Using the appropriate ‘kinase inactive’ mutant receptors, we show that ligand-induced activation of Met results in transphosphorylation of Ron, and vice versa. Transphosphorylation is direct, as it occurs in Met or Ron receptors lacking the docking sites for signal transducers. Phosphate groups are transferred to the tyrosine phosphorylation sites responsible both for kinase up-regulation (Met: Y1234/Y1235 and Ron: Y1238/Y1239) and for generation of signal transducer docking sites (Met: Y1349/Y1356 and Ron Y1353/Y1360). The transphosphorylation specifically takes place for the receptor subfamily, as it is not observed between Met or Ron and ErbB1, ErbB2 or TrkA. Cross-linking experiments show that non-covalent Met-Ron complexes are present on the cell surface, before ligand-induced dimerization. Co-expression of a kinase inactive Ron receptor with naturally-occurring oncogenic Met mutants suppresses the transforming phenotype, suggesting a dominant negative role for the inefficient kinase partner. These data show that, while specific for their ligands, scatter factor receptors cross-talk and cooperate in intracellular signaling.

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Acknowledgements

We are grateful to Y Yarden for supervising part of this work and for critical reading of the manuscript. We thank S Giordano, P Michieli and A Bardelli for advice and criticism and E Wright and A Cignetto for editing and secretarial help. The excellent technical assistance of R Albano, L Palmas and G Petruccelli is also acknowledged. 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. A Follenzi was recipient of a FIRC fellowship to visit the Weizmann Institute of Science, Rehovot, Israel. P Gual is supported by Marie Curie TMR fellowship.

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

    A Follenzi, S Bakovic, P Gual, M C Stella, P Longati & P M Comoglio

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Follenzi, A., Bakovic, S., Gual, P. et al. Cross-talk between the proto-oncogenes Met and Ron. Oncogene 19, 3041–3049 (2000). https://doi.org/10.1038/sj.onc.1203620

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