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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 TGF_α_ 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. Access through your institution Buy or subscribe This is a preview of
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ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS EPH RECEPTORS AND EPHRINS IN
CANCER PROGRESSION Article 23 November 2023 THE EMERGING ROLES OF GΑ12/13 PROTEINS ON THE HALLMARKS OF CANCER IN SOLID TUMORS Article Open access 23 October 2021 FIBROBLAST GROWTH FACTOR
RECEPTORS IN CANCER: GENETIC ALTERATIONS, DIAGNOSTICS, THERAPEUTIC TARGETS AND MECHANISMS OF RESISTANCE Article Open access 03 December 2020 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 REFERENCES * Bue P, Wester K, Sjostrom A, Holmberg A, Nilsson S, Carlsson J,
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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. AUTHOR
INFORMATION Author notes * Andreas Gschwind Present address: Genentech Inc., Department of Immunology, South San Francisco, CA, 94080, USA AUTHORS AND AFFILIATIONS * Department of Molecular
Biology, Max-Planck Institute of Biochemistry, Martinsried, D-82152, Germany Beatrix Schäfer, Andreas Gschwind & Axel Ullrich Authors * Beatrix Schäfer View author publications You can
also search for this author inPubMed Google Scholar * Andreas Gschwind View author publications You can also search for this author inPubMed Google Scholar * Axel Ullrich View author
publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Axel Ullrich. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS
ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 06 June 2003 * Revised: 28 August 2003 * Accepted: 17 October 2003 * Published:
01 December 2003 * Issue Date: 29 January 2004 * DOI: https://doi.org/10.1038/sj.onc.1207278 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:
Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * EGFR
* GPCR * transactivation * LPA * invasion * metalloproteinase