Abstract
Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)-EPH receptor A2 (EPHA2), EGFR-vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2-VEGFR2, EPHA2-fibroblast growth factor receptor 1 (FGFR1), EPHA2-FGFR2, EPHA2-FGFR3, VEGFR2-FGFR1, VEGFR2-FGFR2, and VEGFR2-FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.
Highlights
The 58 human receptor tyrosine kinases (RTKs) are grouped into 20 subfamilies based on the homology of their N-terminal extracellular (EC) domains [1,2,3,4]
We study the heterointeractions of nine RTK pairs (EGFR–EPH receptor A2 (EPHA2), epidermal growth factor receptor (EGFR)–vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2–VEGFR2, EPHA2–fibroblast growth factor receptor 1 (FGFR1), EPHA2–FGFR2, EPHA2–FGFR3, VEGFR2– FGFR1, VEGFR2–FGFR2, and VEGFR2–FGFR3) using a fluorescence-based method: fully quantified spectral imaging Förster resonance energy transfer (FSI-FRET)
We demonstrate that RTKs from unrelated subfamilies can interact with each other in the absence of ligand using a quantitative FRET technique that reports on the heterointeraction strength in live cells
Summary
The 58 human receptor tyrosine kinases (RTKs) are grouped into 20 subfamilies based on the homology of their N-terminal extracellular (EC) domains [1,2,3,4]. A recent review of the literature identified nearly 100 studies that support the idea that RTKs from different subfamilies can interact [27] Despite these studies, heterodimerization across subfamilies has largely been ignored, both in conceptual models of RTK signaling and in the interpretation of RTK signaling data. It can be expected that such conditions (high RTK expression and no ligand) favor the formation of heterodimers of unrelated RTKs, as these RTKs typically do not share ligands It is currently not clear how likely cross-subfamily heterointeractions are to occur, and it is difficult to say how significant a role they play in RTK signaling. This work underscores the significance of heterointeractions in RTK signaling and highlights a method that can be used to study a multitude of interactions in the plasma membrane of live cells
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