Inactivation of platelet-derived growth factor-BB following modification by ADP-ribosyltransferase
| Autor: | Barbara A. Saxty, Paul D. Upton, John MacDermot, Stephen R. Johnstone, Masoud Yadollahi-Farsani |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Pharmacology
Platelet-derived growth factor biology Growth factor medicine.medical_treatment Chinese hamster ovary cell NAD+ ADP-Ribosyltransferase Skeletal muscle Cell biology chemistry.chemical_compound medicine.anatomical_structure Biochemistry chemistry biology.protein medicine Extracellular Fibroblast Platelet-derived growth factor receptor |
| Zdroj: | British Journal of Pharmacology. 133:1219-1226 |
| ISSN: | 0007-1188 |
| DOI: | 10.1038/sj.bjp.0704187 |
| Popis: | Arginine-specific ADP-ribosyltransferase (ART1) is expressed on the surface of a number of cell types, and catalyses the transfer of ADP-ribose from NAD+ to target proteins. We investigated whether extracellular proteins such as growth factors may serve as substrates for this enzyme, with subsequent alteration in their biological activity. Experiments were performed with rat skeletal muscle membranes and V79 Chinese hamster lung fibroblasts with doxycycline-inducible expression of human ART. From a panel of growth factors, platelet-derived growth factor-BB (PDGF-BB) was found to be the best substrate for ART1, whereas the structural homologue PDGF-AA was not a substrate. Under conditions of maximum labelling 5 mol ADP-ribose was incorporated per mol of PDGF-BB. Purified (ADP-ribosyl)-PDGF-BB did not stimulate a mitogenic or chemotactic response in human pulmonary smooth muscle cells, and showed a reduced capacity to bind to PDGF receptors in competition binding experiments, when compared to unmodified PDGF-BB. PDGF-dependent [3H-methyl]-thymidine incorporation was measured in the ART1-transfected fibroblast cell line at physiological concentrations of PDGF-BB, and without addition of extracellular NAD+. Fibroblasts expressing human ART1 at the cell surface showed reduced mitogenic responses to PDGF-BB, but not to PDGF-AA. This loss of mitogenic response in cells expressing ART1 activity was reversed by the addition of agmatine (an ART1 substrate). In conclusion, we propose that PDGF-BB-dependent signalling may be regulated by post-translational modification of the growth factor by ART1 at the cell surface. This has been demonstrated in membranes of rat skeletal muscle, and the reaction confirmed in ART1-transfected fibroblasts. British Journal of Pharmacology (2001) 133, 1219–1226; doi:10.1038/sj.bjp.0704187 |
| Databáze: | OpenAIRE |
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