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Differential Regulation of EGF Receptor Internalization and Degradation by Multiubiquitination within the Kinase Domain

Huang, Fangtian, Kirkpatrick, Donald, Jiang, Xuejun, Gygi, Steven, Sorkin, Alexander·2006·Molecular Cell
DOI 10.1016/j.molcel.2006.02.018
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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.

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Research works printed but not linked: 38

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Metadata

Authors
Huang, F., Kirkpatrick, D., Jiang, X., Gygi, S., & Sorkin, A.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2006-03
Volume
21
Issue
6
Pages
737-748
ISSN
1097-2765
DOI
10.1016/j.molcel.2006.02.018
Cited by
497
References
1
Language
en
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