Huang, F., Kirkpatrick, D., Jiang, X., Gygi, S. & Sorkin, A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol. Cell 21, 737-748

Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, 80045, USA.
Molecular Cell (Impact Factor: 14.02). 04/2006; 21(6):737-48. DOI: 10.1016/j.molcel.2006.02.018
Source: PubMed


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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    • "Ubiquitinylation is a dynamic process and protein eventual protein destination depends on the lysine to which it is attached and whether it is monoubiquitinylated, homopolyubiquitinylated , or hetero-polyubiquitinylated [58, 59]. The UBE2v2 preferentially ubiquitinylates Lys63, which is reported to participate in chaperoning proteins for DNA repair, lysosomal degradation of epidermal growth factor receptors, and NF-κB activation by degradation of class I major histocompatibility complex molecules [60] [61] [62] [63]. Here, protein levels of UBE2v2 were increased in the intermediate age group, while phosphorylation levels were decreased in the intermediate and oldest age groups. "
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