Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors
| Autor: | Axel Ullrich, F. U. Weiss, Henrik Daub, Christian Wallasch |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Endothelin Receptor Antagonists
Lipopolysaccharides Transcriptional Activation Receptor ErbB-2 Peptides Cyclic Receptor tyrosine kinase Cell Line GTP-Binding Proteins Animals Humans Phosphorylation G protein-coupled receptor Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Multidisciplinary biology Endothelins Receptor transactivation Thrombin Recombinant Proteins Rats Enzyme Activation ErbB Receptors Mitogen-activated protein kinase Calcium-Calmodulin-Dependent Protein Kinases biology.protein Cancer research Tyrosine GRB2 Mitogen-Activated Protein Kinases Signal transduction Proto-Oncogene Proteins c-fos Tyrosine kinase Cell Division Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | Nature. 379:557-560 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/379557a0 |
| Popis: | 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 pathway. 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 beta gamma subunits of heterotrimeric G-proteins and as-yet unidentified tyrosine kinases. 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. |
| Databáze: | OpenAIRE |
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