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The Semaphorin 4D receptor controls invasive growth by coupling with Met

Nature Cell Biology volume 4, pages 720–724 (2002)Cite this article

Abstract

Semaphorins are cell surface and soluble signals that control axonal guidance1,2. Recently, semaphorin receptors (plexins) have been discovered and shown to be widely expressed3,4,5. Their biological activities outside the nervous system and the signal transduction mechanism(s) they utilize are largely unknown. Here, we show that in epithelial cells, Semaphorin 4D (Sema 4D) triggers invasive growth, a complex programme that includes cell–cell dissociation, anchorage-independent growth and branching morphogenesis6. Interestingly, the same response is also controlled by scatter factors through their tyrosine kinase receptors, which share striking structural homology with plexins in their extracellular domain 3. We found that in cells expressing the endogenous proteins, Plexin B1 (the Sema 4D Receptor) and Met (the Scatter Factor 1/ Hepatocyte Growth Factor Receptor) associate in a complex. In addition, binding of Sema 4D to Plexin B1 stimulates the tyrosine kinase activity of Met, resulting in tyrosine phosphorylation of both receptors. Finally, cells lacking Met expression do not respond to Sema 4D unless exogenous Met is expressed. This work identifies a novel biological function of semaphorins and suggests the involvement of an unexpected signalling mechanism, namely, the coupling of a plexin to a tyrosine kinase receptor.

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Figure 1: Sema 4D stimulates invasive growth in epithelial cells.
Figure 2: Met associates with Plexin B1 and is activated in response to Sema 4D.
Figure 3: Sema 4D requires Met kinase activity to induce biological responses.
Figure 4: Sema 4D and SF-1 cooperate to induce invasive growth in MLP29 cells.

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Acknowledgements

We thank P. Gual for suggestions and helpful discussions and S. Anguissola for providing MLP29 cells expressing exogenous Plexin B1. We are grateful to M. Geuna and L. Granziero for performing FACS analysis and cell sorting, to S. Gamberini for providing the Trk–Sep chimaera, to T. Nagase for the Plexin D1 cDNA and to L. Naldini for the lentiviral vector p156RRLsinPPThCMVMCSpre. The excellent technical assistance of L. Palmas and R. Albano is gratefully acknowledged. We thank A. Cignetto for secretarial help and E. Wright for editing the manuscript. This work was supported by grants from the Associazione Italiano Ricerca sul Cancro, BIOMED EC and the Harvard-Armenise Foundation grants (P.M.C.) from Telethon-Italy (grant E1129 to L.T.) and from MURST COFIN (S.G). S.A. is recipient of a Federazione Italiano Ricerca sul Cancro fellowship.

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

    Silvia Giordano, Simona Corso, Paolo Conrotto, Stefania Artigiani, Giorgio Gilestro, Davide Barberis, Luca Tamagnone & Paolo M. Comoglio

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  1. Silvia Giordano
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  7. Luca Tamagnone
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  8. Paolo M. Comoglio
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Correspondence to Silvia Giordano.

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Giordano, S., Corso, S., Conrotto, P. et al. The Semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4, 720–724 (2002). https://doi.org/10.1038/ncb843

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