We will determine the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK lateral dimerization. The six receptors chosen for this study, ErbB1, ErbB2, ErbB3, FGFR1, FGFR2, and FGFR3, have been linked to human pathologies. The contributions of the different domains in these six RTKs to the dimerization free energies are currently unknown, mainly due to experimental challenges in the study of full-length RTKs, and membrane proteins in general. Here we will use a novel experimental approach, based on quantitative FRET, which yields dimerization thermodynamics in plasma membranes derived from mammalian cells. The work proposed here is the first step towards comprehensive characterization of the interplay between the different RTK domains in signaling. It will provide basic knowledge regarding the role of the different domains in the dimerization process, and thus aid in the development of highly specific therapeutics which can be used to treat cancers and growth disorders.
RTK domains and RTK dimerization thermodynamics Narrative Many pathologies are believed to occur due to disregulation of ligand-independent RTK dimerization. Here we will gain insight into this process by determining the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK dimerization. The proposed work will aid in the development of highly specific therapeutics that can be used to treat cancers and growth disorders.
| 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 |
| 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; 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 |
| 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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