Dimerization drives PDGF receptor endocytosis through a C-terminal hydrophobic motif shared by EGF receptor.

Like many other receptor tyrosine kinases (RTKs), platelet-derived growth factor (PDGF) receptor beta (PDGFR-beta) is internalized and degraded in lysosomes in response to PDGF stimulation, which regulates many aspects of cell signalling. However, little is known about the regulation of PDGFR-beta endocytosis. Given that ligand binding is essential for the rapid internalization of RTKs, the events induced by the ligand binding likely contribute to the regulation of ligand-induced RTK internalization. These events include receptor dimerization, activation of intrinsic tyrosine kinase activity and autophosphorylation. In this communication, we examined the role of PDGFR-beta kinase activity, PDGFR-beta dimerization and PDGFR-beta C-terminal motifs in PDGF-induced PDGFR-beta internalization. We showed that inhibition of PDGFR-beta kinase activity by chemical inhibitor or mutation did not block PDGF-induced PDGFR-beta endocytosis, suggesting that the kinase activity is not essential. We further showed that dimerization of PDGFR-beta is essential and sufficient to drive PDGFR-beta internalization independent of PDGFR-beta kinase activation. Moreover, we showed that the previously reported 14 amino acid sequence 952-965 is required for PDGF-induced PDGFR-beta internalization. Most importantly, we showed that this PDGFR-beta internalization motif is exchangeable with the EGFR internalization motif (1005-1017) in mediating ligand-induced internalization of both PDGFR-beta and EGFR. This indicates a common mechanism for the internalization of both PDGFR-beta and EGFR.