PMID:16543144

Citation	Huang, F, Kirkpatrick, D, Jiang, X, Gygi, S and Sorkin, A (2006) Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol. Cell 21:737-48
Abstract	Ubiquitination of the EGF receptor (EGFR) is believed to play a critical role in regulating both its localization and its stability. To elucidate the role of EGFR ubiquitination, tandem mass spectrometry was used to identify six distinct lysine residues within the kinase domain of the EGFR, which can be conjugated to ubiquitin following growth factor stimulation. Substitution of these lysine residues with arginines resulted in a dramatic decrease in overall ubiquitination but preserved normal tyrosine phosphorylation of EGFR. Ubiquitination-deficient EGFR mutants displayed a severe defect in their turnover rates but were internalized at rates comparable to those of wild-type receptors. Finally, quantitative mass spectrometry demonstrated that more than 50% of all EGFR bound ubiquitin was in the form of polyubiquitin chains, primarily linked through Lys63. Taken together, these data provide direct evidence for the role of EGFR ubiquitination in receptor targeting to the lysosome and implicate Lys63-linked polyubiquitin chains in this sorting process.
Links	PubMed Online version:10.1016/j.molcel.2006.02.018
Keywords	Amino Acid Sequence; Amino Acid Substitution; Animals; Cell Line; Endocytosis; GRB2 Adaptor Protein/physiology; Lysine/metabolism; Molecular Sequence Data; Phosphorylation; Phosphotransferases/chemistry; Protein Binding; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-cbl/physiology; Receptor, Epidermal Growth Factor/genetics; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction; Swine; Transfection; Ubiquitin/chemistry; Ubiquitin/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:Q504U8		GO:0006898: receptor-mediated endocytosis	ECO:0000314:		P		Figure 5 & 6	complete CACAO 3277
HUMAN:Q504U8	involved_in	GO:0006898: receptor-mediated endocytosis	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:Q05D76		GO:0005769: early endosome	ECO:0000314:		C		Figure 7	complete CACAO 3372
HUMAN:Q05D76	part_of	GO:0005769: early endosome	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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