Trafficking dynamics of VEGFR1, VEGFR2, and NRP1 in human endothelial cells

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • Sarabipour S.
    • Other Affiliation: Johns Hopkins University
  • Kinghorn K.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Quigley K.M.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Kovacs-Kasa A.
    • Other Affiliation: Augusta University
  • Annex B.H.
    • Other Affiliation: Augusta University
  • Bautch V.L.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Gabhann F.M.
    • Other Affiliation: Johns Hopkins University
Abstract
  • The vascular endothelial growth factor (VEGF) family of cytokines are key drivers of blood vessel growth and remodeling. These ligands act via multiple VEGF receptors (VEGFR) and co-receptors such as Neuropilin (NRP) expressed on endothelial cells. These membrane- associated receptors are not solely expressed on the cell surface, they move between the surface and intracellular locations, where they can function differently. The location of the receptor alters its ability to 'see' (access and bind to) its ligands, which regulates receptor activation; location also alters receptor exposure to subcellularly localized phosphatases, which regulates its deactivation. Thus, receptors in different subcellular locations initiate different signaling, both in terms of quantity and quality. Similarly, the local levels of co-expression of other receptors alters competition for ligands. Subcellular localization is controlled by intracellular trafficking processes, which thus control VEGFR activity; therefore, to understand VEGFR activity, we must understand receptor trafficking. Here, for the first time, we simultaneously quantify the trafficking of VEGFR1, VEGFR2, and NRP1 on the same cells-specifically human umbilical vein endothelial cells (HUVECs). We build a computational model describing the expression, interaction, and trafficking of these receptors, and use it to simulate cell culture experiments. We use new quantitative experimental data to parameterize the model, which then provides mechanistic insight into the trafficking and localization of this receptor network. We show that VEGFR2 and NRP1 trafficking is not the same on HUVECs as on non-human ECs; and we show that VEGFR1 trafficking is not the same as VEGFR2 trafficking, but rather is faster in both internalization and recycling. As a consequence, the VEGF receptors are not evenly distributed between the cell surface and intracellular locations, with a very low percentage of VEGFR1 being on the cell surface, and high levels of NRP1 on the cell surface. Our findings have implications both for the sensing of extracellular ligands and for the composition of signaling complexes at the cell surface versus inside the cell.
Date of publication
Keyword
DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
License
  • Attribution 4.0 International
Journal title
  • PLoS Computational Biology
Journal volume
  • 20
Journal issue
  • 2-Feb
Language
  • English
Version
  • Publisher
ISSN
  • 1553-734X
Publisher
  • Public Library of Science

Relations

Parents:

This work has no parents.

In Collection:

Items

Thumbnail Title Date Uploaded Visibility Actions
file details journal.pcbi.1011798.pdf 2024-03-04 Public Download