Inefficient ubiquitination of ligand-responsive p-6Y-EGFR mutants by p-Y371-CBL

Stable Identifier
Reaction [transition]
Homo sapiens
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Phosphorylated CBL does not ubiquitinate EGFR kinase domain mutants efficiently, which enables mutant proteins to escape degradation. There are indications that phosphorylated CBL shows decreased affinity for EGFR kinase domain mutants compared to wild-type EGFR proteins, and quickly dissociates, before ubiquitination is completed. This decreased affinity may be due to altered structure of EGFR kinase domain mutants or to the presence of the chaperone protein HSP90 in complex with the mutant protein. Weaker afinity for phosphorylated CBL was directly demonstrated for EGFR L858R mutant (Yang et al. 2006), and poor ubiquitination inspite of CBL binding was shown for EGFR L858R and EGFR E746_A750del mutants (Yang et al. 2006, Padron et al. 2007). Association of HSP90 with active dimers of phospho-EGFR KD mutants negatively affects phospho-CBL-mediated ubiquitination of EGFR. Binding of HSP90 may decrease the affinity of active dimers of phospho-EGFR KD mutants for phospho-CBL, so that CBL dissociates from the complex upon phosphorylation and cannot perform ubiquitination.
Literature References
PubMed ID Title Journal Year
17699773 Epidermal growth factor receptors with tyrosine kinase domain mutations exhibit reduced Cbl association, poor ubiquitylation, and down-regulation but are efficiently internalized

Roth, MG, Sato, M, PadrĂ³n, D, Shay, JW, Minna, JD, Gazdar, AF

Cancer Res 2007
16849543 Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors

Qu, S, Perez-Tores, M, Sawai, A, Yang, S, Arteaga, CL, Solit, DB, Rosen, N

Cancer Res 2006
Catalyst Activity

ubiquitin protein ligase activity of Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL [plasma membrane]

This event is regulated
Normal reaction
Functional status

Loss of function of Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL [plasma membrane]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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