FGF receptors ubiquitylation: dependence on tyrosine kinase activity and role in downregulation.
A crucial aspect of ligand-mediated receptor activation and shut-down is receptor internalization and degradation. Here we compared the ubiquitylation of either wild type or a K508A 'kinase-dead' mutant of fibroblast growth factor receptor 3 (FGFR3) with that of its naturally occurring overactive mutants, G380R as in achondroplasia, or K650E involved in thanatophoric dysplasia. Fibroblast growth factor receptors ubiquitylation was found to be directly proportional to their intrinsic tyrosine kinase activity, both of which could be blocked using kinase inhibitors. Despite excessive ubiquitylation, both overactive mutants failed to be efficiently degraded, even when challenged with ligand or overexpression of c-Cbl, a putative E3 ligase. We conclude that phosphorylation is essential for FGFR3 ubiquitylation, but is not sufficient to induce downregulation of its internalization resistant mutants.
Monsonego-Ornan
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E
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Adar
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R
Rom
E
E
Yayon
A
A
D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013796:Thanatophoric Dysplasia / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D009097:Multienzyme Complexes; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D025801:Ubiquitin; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex