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Tethering of the platelet-derived growth factor beta receptor to g-protein-coupled receptors : a novel platform for integrative signaling by these receptor classes in mammalian cells

Alderton, Forbes and Rakhit, Soma and Kong, Kok Choi and Palmer, Timothy and Sambi, Balwinder and Pyne, Nigel and Pyne, Susan (2001) Tethering of the platelet-derived growth factor beta 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. ISSN 0021-9258

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Abstract

Here we provide evidence to show that the platelet-derived growth factor β 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 β 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 β-arrestin I can associate with the platelet-derived growth factor β 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 β receptor signaling may be initiated by G-protein-coupled receptor kinase 2/β-arrestin I that has been recruited to the platelet-derived growth factor β 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.