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Hepatocyte Growth Factor/Scatter Factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner

Oncogene volume 20, pages 3735–3745 (2001)Cite this article

Abstract

The Hepatocyte Growth Factor receptor transduces proliferating and scattering signals in epithelial and endothelial cells. We have explored potential interactions of the HGF/SF receptor beta-subunit (p145β MET) with F-actin binding partners aiming to identify novel downstream effectors implicated in HGF/SF pluripotent signalling. Cortactin, a p80/85 F-actin binding protein, was found phosphorylated on tyrosine in response to HGF-SF in A431 human epidermoid carcinoma cells, expressing the HGF/SF receptor (c-MET). The HGF/SF receptor was enriched in the detergent-insoluble fraction and was found to co-precipitate with cortactin and to associate in vitro with cortactin. The Grb2 small adapter protein known to associate via its Src homology 2 domain (SH2) with the MET C-terminus, was also associated with cortactin. Transient transfection of A431 cells with dominant-negative Grb2 constructs has revealed that the Grb2-C-SH3 domain possesses a central role in cortactin phosphorylation in response to HGF/SF. Finally, tyrosine phosphorylation of cortactin was found uncoupled of endogenous c-Src kinase activity, thus further supporting the hypothesis that cortactin is a direct target of the MET kinase. We propose that cortactin may constitute a docking site for MET-derived signals within the cytoskeleton.

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Acknowledgements

We are grateful to JT Parsons and S Weed (Virginia, USA) for the 4F11 and helpful suggestions. We also thank H Meisner, B Mayer (Massachusetts, USA), R Schwall (Genentech Inc., USA) and X Zhan for the GST-Grb2, the dominant-negative Grb2 constructs, recombinant HGF and Myc-Cortacin constructs, respectively. We are also indebted to Prof Joyce Taylor-Papadimitriou and Dr G Panayotou for support and critical reading of the manuscript. This project was partially supported by a G.O.C.O.-1207/001 grant to GG Skouteris. L Crostella is a recipient of Australian Society for Gastroenterology/UCL Medical School Clinical Research Scholarship.

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Author notes

  1. Luca Crostella and Sukhwinderjit Lidder: L Crostella and S Lidder have equally contributed to this study

Authors and Affiliations

  1. Department of Medicine, Laboratory of Cell Biology, Institute of Hepatology, Royal Free and University College London Medical School, London, WC1E 6HX, UK

    Luca Crostella, Sukhwinderjit Lidder & George G Skouteris

  2. Director, Institute of Hepatology, Royal Free and University College London Medical School, London, WC1E 6HX, UK

    Roger Williams

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  1. Luca Crostella
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  2. Sukhwinderjit Lidder
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  3. Roger Williams
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  4. George G Skouteris
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Correspondence to George G Skouteris.

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Crostella, L., Lidder, S., Williams, R. et al. Hepatocyte Growth Factor/Scatter Factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner. Oncogene 20, 3735–3745 (2001). https://doi.org/10.1038/sj.onc.1204474

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