Binding of CBL to ligand-responsive p-6Y-EGFR mutants

Stable Identifier
Reaction [binding]
Homo sapiens
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CBL binds to phosphorylated tyrosine Y1069 (i.e. Y1045 in the mature protein) residue of EGFR cancer mutants. Phosphorylation of Y1045 (corresponding to Y1069 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Greulich et al. 2005, Choi et al. 2007); EGFR G719S mutant (Sordella et al. 2004, Greulich et al. 1005, Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Choi et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005; Xu et al. 2007); EGFR K739_I744dup mutant (Xu et al. 2007); EGFR A767_V769dup mutant (Xu et al. 2007). Very little if any phosphorylation of Y1045 was shown in EGFR T263P mutant (Lee et al. 2006) and EGFR N771_H773dup mutant (Xu et al. 2007). Direct binding of CBL was demonstrated for the EGFR L858R mutant (Yang et al. 2006, Padron et al. 2007) and EGFR E746_A750del mutant (Padron et al. 2007). In EGFRvIII mutant, Y1045 (Y1069) is not phosphorylated (Han et al. 2006, Grandal et al. 2007). Han et al. detected no CBL binding to EGFRvIII mutant (Han et al. 2006), while Grandal et al. detected very little binding, which they explained by indirect recruitment of CBL to EGFRvIII through GRB2 (Grandal et al. 2007).
Literature References
PubMed ID Title Journal Year
16969069 Hypophosphorylation of residue Y1045 leads to defective downregulation of EGFRvIII

Zhang, T, Tang, CK, Han, W, Foulke, JG, Yu, H

Cancer Biol Ther 2006
17177598 Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain

Onofrio, R, Yoshimoto, K, Huang, JHY, Liau, LM, Xu, Q, Thomas, RK, Nelson, SF, Lee, JC, Gabriel, S, Paez, JG, Meyerson, M, Ziaugra, L, Yuza, Y, DeBiasi, RM, Peck, TC, King, JC, Feng, WL, Khan, H, Kawaguchi, T, Beroukhim, R, Linhart, DJ, Cloughesy, T, Rao, PN, Sawyers, CL, Getz, G, Sellers, WR, Vivanco, I, Mellinghoff, IK, Leahy, DJ, Pieper, RO, Nghiemphu, P, O'Neill, K, Greulich, H, Mischel, P, Levine, RL, Glatt, KA

PLoS Med 2006
16953218 EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

Mendrola, JM, Choi, SH, Lemmon, MA

Oncogene 2007
16187797 Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants

Feng, WL, Hahn, WC, Chen, TH, Meyerson, M, Frank, DA, Sellers, WR, Jänne, PA, Alvarez, JV, Greulich, H, Bulmer, SE, Zappaterra, M

PLoS Med 2005
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, Padrón, D, Shay, JW, Minna, JD, Gazdar, AF

Cancer Res 2007
15284455 Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways

Bell, DW, Sordella, R, Haber, DA, Settleman, J

Science 2004
17712310 Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition

Kim, YS, Lee, MJ, Beebe, K, Soga, S, Neckers, LM, Trepel, J, Xu, W

Br J Cancer 2007
17372273 EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes

Zandi, R, Willumsen, BM, Poulsen, HS, Pedersen, MW, van Deurs, B, Grandal, MV

Carcinogenesis 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
Normal reaction
Functional status

Gain of function of Ligand-responsive p-6Y-EGFR mutant dimers [plasma membrane]

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