Trans-autophosphorylation of activated ligand-responsive EGFR mutant dimers

Stable Identifier
R-HSA-1169421
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol, plasma membrane, extracellular region
ReviewStatus
5/5
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Trans-autophosphorylation of activated ligand-responsive EGFR mutant dimers
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The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Activation of ligand-responsive EGFR mutants through spontaneous or EGF-induced dimerization results in trans-autophosphorylation of 5 tyrosine residues (Y1016 i.e. Y992 in the mature protein, Y1092 i.e. Y1068 in the mature protein, Y1110 i.e. Y1086 in the mature protein,Y1172 i.e. Y1148 in the mature protein and Y1197 i.e. Y1173 in the mature protein), which enables constitutive receptor signaling as it provides specific binding sites for cytosolic target proteins involved in signal transduction (Zhang et al. 2006, Yun et al. 2007, Sordella et al. 2004, Lee et al. 2006). Tyrosine residue Y1069 i.e. Y1045 in the mature protein, involved in EGFR down-regulation, is usually phosphorylated in ligand-responsive EGFR mutants (Sordella et al. 2004, Lee et al. 2006). The exact phosphorylation pattern has not been examined for each mutant, but is assumed to closely follow, based on existing experimental evidence, the trans-autophosphorylation pattern of the wild-type EGFR.
Literature References
PubMed ID Title Journal Year
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
15284455 Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways

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

Science 2004
17349580 Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity

Li, Y, Meyerson, M, Woo, MS, Boggon, TJ, Greulich, H, Eck, MJ, Yun, CH

Cancer Cell 2007
16777603 An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor

Zhang, X, Kuriyan, J, Shen, K, Cole, PA, Gureasko, J

Cell 2006
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein tyrosine kinase activity of Active dimers of ligand-responsive EGFR mutants [plasma membrane]

Physical Entity
Active dimers of ligand-responsive EGFR mutants [plasma membrane] (Homo sapiens)
Activity
protein tyrosine kinase activity (GO:0004713)
Normal reaction
EGFR autophosphorylation (Homo sapiens)
Functional status

Gain of function of Active dimers of ligand-responsive EGFR mutants [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Orlic-Milacic, M  (2011-11-04)
Reviewed
Greulich, H  (2011-11-15)
Savas, S  (2011-11-15)
Created
Orlic-Milacic, M  (2011-01-18)
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