Structural and functional analysis of ligand-induced polyubiquitination of platelet-derived growth factor receptor

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We have previously reported that the platelet-derived growth factor (PDGF) receptors are polyubiquitinated as a consequence of ligand binding, and have suggested that the ligand-induced receptor ubiquitination plays a negative regulatory role in mitogenic signaling of the receptor, possible by promoting the efficient degradation of the ligand-activated receptor. In the present study, we have showed that, in addition to the PDGF receptors, the receptors for epidermal growth factor, fibroblast growth factor, and colony-stimulating factor-1, are also ubiquitinated after ligand stimulation, suggesting that the ligand-induced receptor ubiquitination is a general phenomenon observed in most of the monomeric receptor tyrosine kinases. Furthermore, we have proved that the ligand-activated and polyubiquitinated PDGF receptor is quickly degraded by 26S proteasomes inside the cells, thereby intracellular signaling by the receptor is terminated. Our present study establishes the biological significance of a novel mechanism for down-regulation of signal transduction by the receptor, namely, ligand-induced ubiquitination and subsequent proteasomal degradation of the monomeric receptor tyrosine kinases.