) The long-term aim of the studies proposed in this application is to determine by X-ray crystallography how EGF induces dimerization of its receptor, and to investigate mechanistic differences between ligand-induced erbB receptor homo- and heterodimerization. A detailed structural understanding of receptor activation will provide the basis for designing novel approaches for reversing inappropriate activation in human cancers. We hope that this will lead to the development of the next generation of erbB2-directed breast cancer treatments. Receptor tyrosine kinases of the epidermal growth factor (EGF) receptor, or erbB receptor family have been implicated in several human cancers. In particular, the second member that is known as erbB2, HER-2, or the Neu oncogene product, is found overexpressed in thirty percent of human breast cancer cases. ErbB2 is the target of several therapeutic strategies, and humanized monoclonal antibodies raised against erbB2 (Herceptin) are now used clinically to treat breast cancer. ErbB2 and its related receptors are thought to contribute to development of breast and other cancers by being activated inappropriately, usually through their over-expression, in turn promoting uncontrolled cell growth. Like other cytokine and growth factor receptors, the erbB receptors are normally activated by homo and/or heterodimerization induced upon ligand binding. Simply raising the levels of erbB2 that are expressed can lead to cell transformation by promoting ligand-independent dimerization and activation of this receptor. A detailed understanding of how growth factor binding controls erbB receptor homo- and heterodimerization will be very important for developing new approaches to control receptor activation when it goes awry. While many growth factors are dimers, and can bind simultaneously to two receptor molecules, the erbB ligands are monomeric and have not been shown to be bivalent. Our previous biophysical studies have shown that the extracellular domain of the EGF receptor (erbBl) dimerizes completely upon EGF binding, and forms a 2:2 EGF:receptor complex. We have crystallized this complex, and propose to determine its structure by X-ray crystallography. Using similar approaches, we also propose to crystallize the extracellular domain of erbB2, which forms ligand-induced hetero-oligomers with other erbB receptors.
| Lemmon, Mark A (2009) Ligand-induced ErbB receptor dimerization. Exp Cell Res 315:638-48 |
| Ferguson, Kathryn M; Berger, Mitchell B; Mendrola, Jeannine M et al. (2003) EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell 11:507-17 |
