Compelling evidence suggests that current structural models of epidermal growth factor receptor (EGFR) signaling are incomplete, as they cannot account for the population of inactive, pre-assembled receptor dimers in cells that exhibit negatively cooperative ligand binding. Thus, rather than proceeding through simple ligand- induced dimerization, EGFR signaling involves the ligand-dependent allosteric regulation of receptor dimers. This proposal describes how I will (i) obtain a thorough structural understanding of pre-assembled EGFR dimers, (ii) identify the conformational changes that switch receptor dimers between the 'off' and 'on' states, and (iii) investigate the much-discussed possibilities of oncogenic mutation- and ligand-specific 'on' states of EGFR that differentially modulate signaling output. My preliminary data shows that the highly-homologous C. elegans EGFR is constitutively dimeric, which circumvents technical challenges associated with human EGFR and provides a unique and straightforward opportunity to answer these important mechanistic questions. Since excessive EGFR signaling drives many human cancers, the results will provide the conceptual framework for designing a new generation of 'smarter' EGFR-targeted cancer therapies.
Excessive proliferative signaling by the epidermal growth factor receptor (EGFR) drives the onset and progression of many aggressive and deadly cancers. Some EGFRs float around the cell membrane freely prior to stimulation, but a fraction of EGFRs collide and stick together, which creates distinct signaling consequences upon stimulation. This project attempts to understand the molecular architecture of the subset of stuck-together EGFRs, and how they are switched 'on' and 'off', with a view towards providing new strategies for inhibiting EGFR signaling in cancer.
| Freed, Daniel M; Bessman, Nicholas J; Kiyatkin, Anatoly et al. (2017) EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 171:683-695.e18 |
| Lemmon, Mark A; Freed, Daniel M; Schlessinger, Joseph et al. (2016) The Dark Side of Cell Signaling: Positive Roles for Negative Regulators. Cell 164:1172-1184 |
| Freed, Daniel M; Alvarado, Diego; Lemmon, Mark A (2015) Ligand regulation of a constitutively dimeric EGF receptor. Nat Commun 6:7380 |
| 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 |
