A tyrosine residue in the juxtamembrane segment of the platelet-derived growth factor beta-receptor is critical for ligand-mediated endocytosis.
The importance of tyrosine residues in ligand-mediated endocytosis of the platelet-derived growth factor beta-receptor was analyzed using a series of tyrosine residue-mutated beta-receptors, which together cover all of the tyrosine residues in the juxtamembrane segment, the kinase insert, and the carboxyl-terminal tail; also certain of the tyrosine residues within the first and second parts of the kinase domain were examined. Of all of these tyrosine residues, only Tyr-579 seemed to be important for internalization, since mutation of this residue resulted in substantial reduction in the rate of ligand-induced receptor internalization (approximately 60% of the wild-type level). Replacement of Tyr-579 by either an aromatic (Phe) or a nonaromatic (Asp) residue reduced the efficiency of the mutant receptors in internalization to the same extent, suggesting that the role of Tyr-579 in the beta-receptor is different from that of the previously described tyrosine-based internalization motifs, which were first determined for the low density lipoprotein receptor. Tyr-579 has been found to be an autophosphorylation site in the beta-receptor. Moreover, the internalization rate of a kinase negative receptor mutant was not altered by the additional mutation of Tyr-579. Thus, it is likely that phosphorylation of Tyr-579 is important for ligand-induced internalization of the beta-receptor.
Mori
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S
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
Rönnstrand
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Claesson-Welsh
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Heldin
C H
CH
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta; D000077214:Becaplermin; D002999:Clone Cells; D004705:Endocytosis; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D017527:Receptor, IGF Type 2 / Q000737:chemistry; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013552:Swine; D014162:Transfection; D014443:Tyrosine
D007457:Iodine Radioisotopes; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D000077214:Becaplermin; D014443:Tyrosine; D017479:Receptors, Platelet-Derived Growth Factor