Receptor Tyrosine Kinases (RTKs) regulate cell growth, differentiation, and motility. Aberrant RTK signaling can lead to disease, and RTK-specific therapies are being sought. Yet, there is no consensus model of RTK signal transduction across the plasma membrane, and the lack of basic knowledge is a bottleneck in further development and improvement of RTK-specific therapies. Two models are most often discussed in the literature, the diffusion-based or canonical model, or the pre-formed dimer model, which differ in the absence and presence of unliganded dimers. Here we explore the novel concept that most RTKs follow a universal activation mechanism, with the difference rooted in the exact value of the unliganded dimerization constant, rather than the fundamental receptor behavior. To test this concept, here we will establish a methodology that, for the first time, allows quantitative RTK dimerization measurements for physiological expression levels. We will characterize the stability of several RTK unliganded dimers in native plasma membranes, and we will assess whether their behavior is described by the law of mass action. We will assess the ability of ligands to induce structural changes in the RTK dimers, independent of the exact values of the unliganded dimer stabilities, in accord with the idea of a universal model of RTK activation. A universal model will provide a unified framework for understanding the similarities and differences in RTK activity. It will help us transition from qualitative to quantitative understanding of RTK signal transduction with predictive power. In the long run, this basic knowledge will help the scientific community in the search for novel RTK-inhibitors that can be used to combats human cancers and growth disorders.
Aberrant Receptor Tyrosine Kinase (RTK) signaling can lead to disease, and RTK-specific therapies are being sought. Yet, there is no consensus model of RTK signal transduction across the plasma membrane, and the lack of basic knowledge is a bottleneck in further development and improvement of RTK-specific therapies. Here we explore the novel concept that most RTKs follow a universal activation mechanism, with the difference rooted in the exact value of the unliganded dimerization constant, rather than the fundamental receptor behavior.
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| 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 |
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| 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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