Alderton, F., Rakhit, S., Kong, K.C., Palmer, T., Sambi, B., Pyne, S. and Pyne, N.J. (2001) Tethering of the platelet-derived growth factor ß receptor to G-protein-coupled receptors - A novel platform for integrative signaling by these receptor classes in mammalian cells. Journal of Biological Chemistry, 276, pp. 28578-28585. (doi: 10.1074/jbc.M102771200)
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Publisher's URL: http://dx.doi.org/10.1074/jbc.M102771200
Abstract
Here we provide evidence to show that the platelet-derived growth factor ß receptor is tethered to endogenous G-protein-coupled receptor(s) in human embryonic kidney 293 cells. The tethered receptor complex provides a platform on which receptor tyrosine kinase and G-protein-coupled receptor signals can be integrated to produce more efficient stimulation of the p42/p44 mitogen-activated protein kinase pathway. This was based on several lines of evidence. First, we have shown that pertussis toxin (which uncouples G-protein-coupled receptors from inhibitory G-proteins) reduced the platelet-derived growth factor stimulation of p42/p44 mitogen-activated protein kinase. Second, transfection of cells with inhibitory G-protein α subunit increased the activation of p42/p44 mitogen-activated protein kinase by platelet-derived growth factor. Third, platelet-derived growth factor stimulated the tyrosine phosphorylation of the inhibitory G-protein α subunit, which was blocked by the platelet-derived growth factor kinase inhibitor, tyrphostin AG 1296. We have also shown that the platelet-derived growth factor ß receptor forms a tethered complex with Myc-tagged endothelial differentiation gene 1 (a G-protein-coupled receptor whose agonist is sphingosine 1-phosphate) in cells co-transfected with these receptors. This facilitates platelet-derived growth factor-stimulated tyrosine phosphorylation of the inhibitory G-protein α subunit and increases p42/p44 mitogen-activated protein kinase activation. In addition, we found that G-protein-coupled receptor kinase 2 and ß-arrestin I can associate with the platelet-derived growth factor ß receptor. These proteins play an important role in regulating endocytosis of G-protein-coupled receptor signal complexes, which is required for activation of p42/p44 mitogen-activated protein kinase. Thus, platelet-derived growth factor ß receptor signaling may be initiated by G-protein-coupled receptor kinase 2/ß-arrestin I that has been recruited to the platelet-derived growth factor ß receptor by its tethering to a G-protein-coupled receptor(s). These results provide a model that may account for the co-mitogenic effect of certain G-protein-coupled receptor agonists with platelet-derived growth factor on DNA synthesis.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Palmer, Dr Timothy |
Authors: | Alderton, F., Rakhit, S., Kong, K.C., Palmer, T., Sambi, B., Pyne, S., and Pyne, N.J. |
Subjects: | Q Science > QR Microbiology |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences |
Journal Name: | Journal of Biological Chemistry |
Journal Abbr.: | J Biol Chem. |
Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN: | 0021-9258 |
ISSN (Online): | 1083-351X |
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