Stimulatory Effect of PDGF on HMG-CoA Reductase Activity and N-Linked Glycosylation Contributes to Increased Expression of IGF-1 Receptors in Human Fibroblasts

Abstract

In the present paper, we show that the prereplicative period in platelet-derived growth factor (PDGF)-stimulated human diploid fibroblasts (HDF) includes an early increase in 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity followed by an increased N-linked glycosylation. HMG-CoA reductase inhibitors abolished these events and also prevented progression of cells into S-phase, indicating that mevalonate (MVA)-dependent glycosylation might be required in PDGF-mediated cell growth. Furthermore, PDGF was demonstrated to increase the number of insulin-like growth factor 1 (IGF-1) binding sites in HDF. This event, which was dependent on MVA, took place late in the prereplicative period and was correlated to a significant increase in the expression ofde novosynthesized IGF-1 receptor (IGF-1R) proteins at the cell membrane. The PDGF-induced IGF-1R expression was suppressed in the presence of tunicamycin, an inhibitor of N-linked glycosylation. Taken together, our findings suggest an important role of MVA and N-linked glycosylation in PDGF-mediated growth activation of HDF.