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Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors

Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors TRANSDUCTION of a mitogenic signal from the cell membrane to the nucleus involves the adapter proteins SHC and Grb2, which mediate activation of the Ras/mitogen-activated protein (MAP) kinase pathway1–5. In contrast to receptor tyrosine kinases (RTKs), the signalling steps leading to Ras/MAP kinase activation by G-protein-coupled receptors (GPCRs) are still poorly characterized but appear to include βγ subunits of heterotrimeric G-proteins and as-yet unidentified tyrosine kinases6–8. We report here that the epidermal growth factor receptor (EGFR) and the neu oncoprotein become rapidly tyrosine-phosphorylated upon stimulation of Rat-1 cells with the GPCR agonists endothelin-1, lysophosphatic acid and thrombin, suggesting that there is an intracellular mechanism for transactivation. Specific inhibition of EGFR function by either the selective tyrphostin AG1478 or a dominant-negative EGFR mutant suppressed MAP kinase activation and strongly inhibited induction of fos gene expression and DNA synthesis. Our results demonstrate a role for RTKs as downstream mediators in GPCR mitogenic signalling and suggest a ligand-independent mechanism of RTK activation through intracellular signal crosstalk. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Springer Journals

Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors

Daub, Henrik; Ulrich Weiss, F.; Wallasch, Christian; Ullrich, Axel
Nature , Volume 379 (6565) – Feb 8, 1996
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References (30)

Publisher
Springer Journals
Copyright
Copyright © 1996 by Nature Publishing Group
Subject
Science, Humanities and Social Sciences, multidisciplinary; Science, Humanities and Social Sciences, multidisciplinary; Science, multidisciplinary
ISSN
0028-0836
eISSN
1476-4687
DOI
10.1038/379557a0
Publisher site
See Article on Publisher Site

Abstract

TRANSDUCTION of a mitogenic signal from the cell membrane to the nucleus involves the adapter proteins SHC and Grb2, which mediate activation of the Ras/mitogen-activated protein (MAP) kinase pathway1–5. In contrast to receptor tyrosine kinases (RTKs), the signalling steps leading to Ras/MAP kinase activation by G-protein-coupled receptors (GPCRs) are still poorly characterized but appear to include βγ subunits of heterotrimeric G-proteins and as-yet unidentified tyrosine kinases6–8. We report here that the epidermal growth factor receptor (EGFR) and the neu oncoprotein become rapidly tyrosine-phosphorylated upon stimulation of Rat-1 cells with the GPCR agonists endothelin-1, lysophosphatic acid and thrombin, suggesting that there is an intracellular mechanism for transactivation. Specific inhibition of EGFR function by either the selective tyrphostin AG1478 or a dominant-negative EGFR mutant suppressed MAP kinase activation and strongly inhibited induction of fos gene expression and DNA synthesis. Our results demonstrate a role for RTKs as downstream mediators in GPCR mitogenic signalling and suggest a ligand-independent mechanism of RTK activation through intracellular signal crosstalk.

Journal

Nature – Springer Journals

Published: Feb 8, 1996

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