Receptor Tyrosine Kinases (RTKs) are single-pass transmembrane proteins that control cell growth, differentiation, motility, and metabolism. They are very promising drug targets, but the incomplete understanding of the activation mechanism of the RTKs in the membrane hinders the development of effective and safe therapies. This proposal is dedicated to the development of new methodologies that can quantify molecular interactions and can move the field forward.
In Aim 1, we will develop a combined Number and Brightness (N&B) and Frster Resonance Energy Transfer (FRET) methodology that yields both the oligomer size and the dissociation constants for full length RTKs in live cells.
In Aim 2, we will develop a fluorescence-based methodology that yields molecular ligand binding constants for full-length RTKs in live cells. Along with enabling the acquisition of new knowledge by the broad scientific community, the work in the aims will yield new insights into critical aspects of the signaling by the RTKs used in method development.
Receptor Tyrosine Kinases (RTKs) are very promising drug targets, but the incomplete understanding of their activation mechanism hinders the development of effective and safe therapies. This proposal is dedicated to the development of new methodologies that can quantify RTK molecular interactions and can move the field forward. Along with enabling the acquisition of new knowledge by the broad scientific community, the proposed work will yield new insights into critical aspects of RTK signaling.
| Singh, Deo R; Kanvinde, Pranjali; King, Christopher et al. (2018) The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures. Commun Biol 1:15 |
| King, Christopher; Wirth, Daniel; Workman, Samuel et al. (2018) Interactions between NRP1 and VEGFR2 molecules in the plasma membrane. Biochim Biophys Acta Biomembr 1860:2118-2125 |
| King, Christopher; Raicu, Valerica; Hristova, Kalina (2017) Understanding the FRET Signatures of Interacting Membrane Proteins. J Biol Chem 292:5291-5310 |
| Wiedman, Gregory; Kim, Sarah Y; Zapata-Mercado, Elmer et al. (2017) pH-Triggered, Macromolecule-Sized Poration of Lipid Bilayers by Synthetically Evolved Peptides. J Am Chem Soc 139:937-945 |
| Singh, Deo R; Ahmed, Fozia; Sarabipour, Sarvenaz et al. (2017) Intracellular Domain Contacts Contribute to Ecadherin Constitutive Dimerization in the Plasma Membrane. J Mol Biol 429:2231-2245 |
| King, Christopher; Wirth, Daniel; Workman, Samuel et al. (2017) Cooperative interactions between VEGFR2 extracellular Ig-like subdomains ensure VEGFR2 dimerization. Biochim Biophys Acta Gen Subj 1861:2559-2567 |
| Del Piccolo, Nuala; Hristova, Kalina (2017) Quantifying the Interaction between EGFR Dimers and Grb2 in Live Cells. Biophys J 113:1353-1364 |
| Del Piccolo, Nuala; Sarabipour, Sarvenaz; Hristova, Kalina (2017) A New Method to Study Heterodimerization of Membrane Proteins and Its Application to Fibroblast Growth Factor Receptors. J Biol Chem 292:1288-1301 |
| King, Christopher; Stoneman, Michael; Raicu, Valerica et al. (2016) Fully quantified spectral imaging reveals in vivo membrane protein interactions. Integr Biol (Camb) 8:216-29 |
| Sarabipour, Sarvenaz; Ballmer-Hofer, Kurt; Hristova, Kalina (2016) VEGFR-2 conformational switch in response to ligand binding. Elife 5:e13876 |
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