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

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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 1083-351X (https://doi.org/10.1074/jbc.M102771200)

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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.

ORCID iDs

Alderton, Forbes, Rakhit, Soma, Kong, Kok Choi, Palmer, Timothy, Sambi, Balwinder, Pyne, Nigel ORCID logoORCID: https://orcid.org/0000-0002-5657-4578 and Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584;
CORE (COnnecting REpositories)