Investigating the Hetero-interactions of Receptor Tyrosine Kinases in Live Cells

Abstract

Receptor tyrosine kinases (RTKs), the second largest class of membrane receptors, transduce signals across the plasma membrane via lateral association. They play an important role in development, regulating tissue growth, and controlling cell migration. Mutations in RTKs are associated with many cancers, and thus anti-RTK drugs are being actively developed and tested. While many drugs have entered the market, they largely have only been moderately successful. One possible explanation for this is a lack of biophysical understanding of how these receptors interact with each other. There is a growing body of evidence that RTKs from different subfamilies (e.g., VEGFs, Ephs, FGFRs) can form hetero-species; however, the current picture of this interactome is rather incomplete. It is possible that presently unknown interactions affect the response of a given RTK to its ligands and inhibitors. Using a quantitative FRET spectroscopy method known as Fully Quantified Spectral Imaging (FSI), we demonstrate the existence of specific interactions between members of different RTK subfamilies. Finally, we present thermodynamic models that show the relative population of heterodimers under different conditions.