Cellular responses to many extracellular factors that control cell growth and differentiation are mediated by the cell-surface receptors with tyrosine kinase activity. The mechanism of transmembrane signaling by receptor tyrosine kinases involves an initial ligand- induced receptor dimerization vent that leads to activation of the intracellular tyrosine kinase domain. For a given class of receptor tyrosine kinases, ligand-induced dimerization can involve two receptors that are the same (homodimerization) or different (heterodimerization). It is now appreciated that heterodimerization provides a mechanism for increasing the diversity of signaling through a given family of receptors. In this proposal, we focus on the four known receptors in the epidermal growth factor (EGF) receptor family - known as erbB1 to erbB4. The erbB receptors have been implicated in a number of human cancers. In particular, erbB2 (also known as Neu, or HER-2) is strongly implicated in breast cancer. It appears that aberrant over expression of a single member of this family can disrupt normal signaling, in some cases leading to uncontrolled cell proliferation. There are at least 12 different ligands that signal through the erbB family of receptor tyrosine kinases, including EGF, TGFalpha, and the neuregulins. The ligands differ in their receptor-heterodimers. Their specific biological activities are thought to arise from these differences. We are interested in understanding how the multiple different ligands induce formation of particular receptor dimers. For EGF receptor, we have shown that the extracellular domain of the receptor is sufficient of ligand-induced dimerization, and that two EGF molecules are required to from the dimer. Through analyses of the other erbB receptor extracellular domains, produced in a baculovirus expression system, we now propose a quantitative comparison of ligand-induced receptor homo- and heterodimerization using biophysical techniques. In addition we propose experiments aimed at determining the structural basis for ligand-induced erbB receptor dimerization. Our ultimate goal is to understand the characteristics of erbB ligands that define which receptor dimers they induce, and how this relates to their specific biological effects. By understanding this, we hope that approaches will be suggested for modulating erbB receptor signaling when it is disrupted in human cancers.
| Ronan, Tom; Macdonald-Obermann, Jennifer L; Huelsmann, Lorel et al. (2016) Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins. J Biol Chem 291:5528-40 |
| Ganetzky, Rebecca; Finn, Erin; Bagchi, Atrish et al. (2015) EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features. Mol Genet Genomic Med 3:452-8 |
| Freed, Daniel M; Alvarado, Diego; Lemmon, Mark A (2015) Ligand regulation of a constitutively dimeric EGF receptor. Nat Commun 6:7380 |
| Bessman, Nicholas J; Bagchi, Atrish; Ferguson, Kathryn M et al. (2014) Complex relationship between ligand binding and dimerization in the epidermal growth factor receptor. Cell Rep 9:1306-17 |
| Bessman, Nicholas J; Freed, Daniel M; Lemmon, Mark A (2014) Putting together structures of epidermal growth factor receptors. Curr Opin Struct Biol 29:95-101 |
| Red Brewer, Monica; Yun, Cai-Hong; Lai, Darson et al. (2013) Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci U S A 110:E3595-604 |
| Park, Jin H; Liu, Yingting; Lemmon, Mark A et al. (2012) Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem J 448:417-23 |
| Park, Jin H; Lemmon, Mark A (2012) Occupy EGFR. Cancer Discov 2:398-400 |
| Shih, Andrew J; Telesco, Shannon E; Choi, Sung-Hee et al. (2011) Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases. Biochem J 436:241-51 |
| Lemmon, Mark A; Schlessinger, Joseph (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117-34 |
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