Epidermal growth factor receptor dimerization

Fan Z, Lu Y, Wu X, et al. Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. JBiol Chem 1994 269 27,595-27,602. 

Brown, P. M., Debanne, M. T., Grothe, S., Bergsma, D., Caron, M., Kay, C., and O Connor-McCourt, M. D. (1994). The extracellular domain of the epidermal growth factor receptor. Studies on the affinity and stoichiometry of binding, receptor dimerization and a binding-domain mutant. Eur.J. Biochem. 225, 223-233. 

Yu, X., Sharma, K. D., Takahashi, T., Iwamoto, R., and Mekada, E. (2002). Ligand-independent dimer formation of epidermal growth factor receptor (EGFR) is a step separable from ligand-induced EGFR signaling. Mol. Biol. Cell 13, 2547-2557. 

Laux, L, Jain, A., Singh, S., Agus, D.B. (2006) Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies. BrJ Cancer, 94 (1), 85-92. 

Liu Y-C, Yen H-Y, Chen C-Y, Chen C-H, Cheng P-F, Juan Y-H, Chen C-H, Khoo K-H, Yu C-J, Yang P-C, Hsu T-L, Wong C-H (2011) Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. Proc Natl Acad Sci USA 108 11332-11337... 

Clayton, A. H. Walker, F. Orchard, S. G. Henderson, C. Fuch, D. Rothacker, J. Nice, E. C. Burgess, A. W. ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor-A multidimentional microscopy analysis. J. Biol. Chem. 2005, 280, 30392-30399. 

Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric state (/eft) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently. The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y) and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins (S). 

The insulin receptor is the prototype for a number of receptor enzymes with a similar structure and receptor Tyr kinase activity. The receptors for epidermal growth factor and platelet-derived growth factor, for example, have structural and sequence similarities to the insulin receptor, and both have a protein Tyr kinase activity that phosphorylates IRS-1. Many of these receptors dimerize after binding ligand the insulin receptor is already a dimer before insulin binds. The binding of adaptor proteins such as Grb2 to (P) Tyr residues is a common mechanism for promoting protein-protein interactions, a subject to which we return in Section 12.5. 

Fig. 6-24 Schematic representation of the epidermal growth factor (EGF) receptor. The receptor is an integral membrane protein with a single transmembrane domain. The ligand binding site is in the extracellular domain and there is a tyrosine kinase domain near the C terminus in the cytoplasm, (a) At rest the receptor exists as single subunits. (b) Upon binding EGF, the receptor forms dimers stabilized by noncovalent associations. After dimerization the activated tyrosine kinase phosphorylates tyrosine residues in the cytoplasmic domain prior to the recruitment of further proteins to bind to the receptor. The formation of a protein assembly on the cytoplasmic domain is necessary for activation of enzymes that regulate cell metabolism and gene transcription.

In one example, the technology was used to study the dimerization of the epidermal growth factor (EGF) receptor. The p-gal mutants were fused to both the extracellular and the transmembrane domains of EGF, and stably expressed in C2C12 cells. The formation of active p-gal was then dependent on the agonist-stimulated dimerization [208]. 

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