Impact of ligand binding on VEGFR1, VEGFR2, and NRP1 localization in human endothelial cells
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View abstract on PubMed
Summary
This summary is machine-generated.Vascular endothelial growth factor receptors (VEGFRs) trafficking is altered by ligand binding, with most signaling complexes forming intracellularly. This intracellular reservoir effect impacts receptor competition and angiogenesis regulation.
Area Of Science
- Molecular and Cellular Biology
- Biophysics
- Biochemistry
Background
- Vascular endothelial growth factor receptors (VEGFRs) are crucial for angiogenesis, with their cell surface availability regulated by intracellular trafficking.
- Previous work quantified differential trafficking of VEGFR1, VEGFR2, and Neuropilin-1 (NRP1) using experimental data and computational modeling.
Purpose Of The Study
- To quantify how different vascular endothelial growth factor (VEGF) ligands alter VEGFR trafficking and signaling complex dynamics.
- To investigate the impact of receptor localization and ligand binding on signal initiation complex localization and dynamics.
Main Methods
- Computational modeling and simulations incorporating experimental data.
- Analysis of four VEGF-A and Placental Growth Factor (PLGF) splice isoforms.
- Parameterization and validation using new experimental data for two specific ligands.
Main Results
- VEGFR2 trafficking is altered by ligand binding (increased internalization), while VEGFR1 trafficking remains unaffected.
- Most ligand-receptor complexes for both VEGFR1 and VEGFR2 are located intracellularly, challenging the canonical cell surface activation model.
- A substantial 'reservoir effect' of intracellular ligand availability influences receptor competition and signaling dynamics, unlike minimal cell surface competition.
Conclusions
- Ligand binding differentially affects VEGFR trafficking, primarily through increased VEGFR2 internalization.
- Intracellular localization of ligand-receptor complexes is significant and plays a key role in receptor competition and signaling.
- Understanding these trafficking dynamics and the 'reservoir effect' is critical for developing therapeutics targeting VEGFR signaling in angiogenesis.
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