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Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion

Oncogene volume 23, pages 991–999 (2004)Cite this article

Abstract

Signalling through G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTK) is involved in the regulation of essential cellular processes and its deregulation is associated with tumorigenesis in vitro and in vivo. We investigated pathophysiological processes that are regulated by GPCR pathways in human kidney and bladder cancer cell lines. Our results show that GPCR ligands induce tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) as well as downstream signalling events such as recruitment of the adapter protein Shc and activation of the mitogen-activated protein kinases (MAPK) ERK1/2, JNK and p38. Moreover, we report that the EGFR transactivation signal involves the EGFR ligands amphiregulin, HB-EGF and TGFα as well as the metalloproteinases ADAM 10, 15 and 17, depending on the cellular system. Finally, we demonstrate that EGFR transactivation is part of a regulatory system that modulates the migratory and invasive behaviour of kidney and bladder cancer cells. In conclusion, our findings demonstrate that metalloproteinase-mediated transactivation of the EGFR is a key mechanism of the cellular signalling network that promotes MAPK activation as well as tumour cell migration and invasion in response to a variety of physiologically relevant GPCR ligands, and therefore represents a novel target for cancer intervention strategies.

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Abbreviations

DMSO:

dimethylsulphoxide

EGFR:

epidermal growth factor receptor

ERK:

extracellular signal-regulated kinase

GPCR:

G-protein-coupled receptor

HB-EGF:

heparin-binding EGF-like growth factor

JNK:

c-jun N-terminal kinase

LPA:

lysophosphatidic acid

MAPK:

mitogen-activated protein kiase

RTK:

receptor tyrosine kinase

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Acknowledgements

We would like to thank Dr Klaus Maskos (Martinsried) for providing batimastat, Stefan Hart for generating the stable A498 clones and Beatrice Marg for carefully reading the manuscript.

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Author notes

  1. Andreas Gschwind

    Present address: Genentech Inc., Department of Immunology, South San Francisco, CA, 94080, USA

Authors and Affiliations

  1. Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried, D-82152, Germany

    Beatrix Schäfer, Andreas Gschwind & Axel Ullrich

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  1. Beatrix Schäfer
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Correspondence to Axel Ullrich.

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Schäfer, B., Gschwind, A. & Ullrich, A. Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. Oncogene 23, 991–999 (2004). https://doi.org/10.1038/sj.onc.1207278

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