title: Dimerization drives PDGF receptor endocytosis through a C-terminal hydrophobic motif shared by EGF receptor.
abstract: 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.
authors.affiliation: Department of Cell Biology and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Justin
authors.initials: J
authors.lastname: Pahara
authors.forename: Huaiping
authors.initials: H
authors.lastname: Shi
authors.forename: Xinmei
authors.initials: X
authors.lastname: Chen
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D019281:Dimerization; D004705:Endocytosis / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010770:Phosphotransferases / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D004791:Enzyme Inhibitors; D010770:Phosphotransferases; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor