Degradation process of ligand-stimulated platelet-derived growth factor β-receptor involves ubiquitin-proteasome proteolytic pathway

Abstract

The platelet-derived growth factor β-receptor undergoes polyubiquitination as a consequence of ligand binding. We have previously reported that ligand-induced ubiquitination of the receptor plays a negative regulatory role in its mitogenic signaling possibly by promoting the efficient degradation of the ligand-activated receptor (Mori, S., Heldin, C.- H., and Claesson-Welsh, L. (1993) J. Biol. Chem. 268, 577-583). In the present study, we have examined effects of different kinds of cell- penetrating proteasome inhibitors, including substrate-related peptidyl aldehydes, Cbz-Ile-Glu(O-t-Bu)-Ala-leucinal (where Bu is butyl and Cbz is benzyloxycarbonyl) (PSI) and Cbz-Leu-Leu-norvalinal (MG115), and a Streptomyces metabolite lactacystin, on degradation of the receptor in intact cells with the aim of evaluating the role of the receptor ubiquitination in the proteasome-dependent proteolytic process. These proteasome inhibitors were found to considerably inhibit ligand-stimulated degradation of the wild- type β-receptor; however, their inhibitory effect was not observed when the cells expressing the ubiquitination-deficient mutant β-receptor were analyzed. These data suggest that the degradation process of the ligand- stimulated β-receptor involves the ubiquitin-proteasome proteolytic pathway.