Cell adhesion regulates ubiquitin-mediated degradation of the platelet-derived growth factor receptor beta.
Cross-talk between integrin-mediated adhesion and growth factors has been described in many recent studies; however, the underlying mechanisms remain incompletely understood. We report here that detachment of cells from the extracellular matrix induced a decrease in both the autophosphorylation and protein levels of the platelet-derived growth factor receptor beta (PDGF-R beta), which was completely reversed upon replating cells on fibronectin. The effect occurred in all cells examined but to a greater extent in primary fibroblasts compared with established cell lines. Decreased PDGF-R levels in suspended cells correlated with ubiquitination of the PDGF-R and was blocked by treatment with inhibitors of the proteasome pathway. Unlike PDGF-induced down-regulation, detachment-induced degradation did not require receptor autophosphorylation, internalization, or tyrosine kinase activity. We conclude that cell detachment results in cellular desensitization to PDGF that is mediated by degradation of the PDGF-R via a novel ubiquitin-dependent pathway.
Baron
V
V
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Schwartz
M
M
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D034281:Dynamins; D004622:Embryo, Mammalian / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005353:Fibronectins; D008024:Ligands; D009097:Multienzyme Complexes; D020032:Tyrphostins; D014452:Ubiquitins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D014357:Trypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; D034281:Dynamins