Raftlin is recruited by neuropilin-1 to the activated VEGFR2 complex to control proangiogenic signaling

Asha Bayliss, Ananthalakshmy Sundararaman, Camille Granet, Harry Mellor*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

33 Downloads (Pure)

Abstract

Background: VEGFR2 (vascular endothelial growth factor receptor 2) is the major pro-angiogenic receptor in endothelial cells. Compared to other members of the receptor tyrosine kinase family, we know relatively few VEGFR2 signaling partners. Our objective was to use mass spectrometry-based proteomics to identify novel binding partners of activated VEGFR2.

Methods: We created an endothelial cell line stably expressing GFP-tagged VEGFR2 and isolated activated receptor complexes. Analysis by mass spectrometry identified raftlin as a novel binding partner of VEGFR2.

Results: We found that raftlin is recruited to the activated VEGFR2 complex via the co-receptor Nrp1 (neuropilin-1). We show that raftlin regulates the surface levels of Nrp1 in endothelial cells, controlling the availability of Nrp1 for VEGFR2 interaction. Raftlin stabilizes active VEGFR2 at the cell surface by inhibiting endocytosis of the activated receptor. Raftlin also promotes recycling of internalized VEGFR2 to the cell surface. Raftlin alters the signaling outcomes of VEGFR2 activation, inhibiting the activation of p38 and FAK (focal adhesion kinases) specifically. Both pathways are linked to cell migration in endothelial cells, and raftlin inhibits endothelial cell migration in response to VEGF.

Conclusion: Nrp1 is an important co-receptor for VEGFR2; however, its functions are still only partially understood. We show that raftlin works with Nrp1 in endothelial cells to control intracellular trafficking of the activated VEGFR2. This modulates the response to VEGF and controls endothelial cell migration.
Original languageEnglish
Number of pages13
JournalAngiogenesis
DOIs
Publication statusPublished - 9 Apr 2020

Keywords

  • VEGF receptor
  • angiogenesis
  • neuropilin
  • endothelial cell
  • intracellular trafficking

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