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Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output

Kurt Ballmer-Hofer1, Anneli E Andersson, Laura E Ratcliffe

  • 1Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institute, Villigen, Switzerland.

Blood
|May 19, 2011
PubMed

Insights

Vascular endothelial growth factor (VEGF) isoforms differentially regulate VEGFR-2 trafficking via neuropilin-1 (NRP-1). NRP-1 binding directs VEGFR-2 recycling, while its absence routes the receptor for degradation, impacting signaling outcomes.

Area of Science:

  • Cell biology
  • Molecular biology
  • Biochemistry

Background:

  • Vascular endothelial growth factors (VEGFs) are key regulators of blood and lymph vessel development.
  • VEGFs signal through receptor tyrosine kinases (RTKs), including VEGFR-2, and coreceptors like neuropilin-1 (NRP-1).
  • Different VEGF-A isoforms exist, potentially leading to distinct signaling pathways.

Purpose of the Study:

  • To investigate how distinct VEGF-A isoforms (VEGF-A(165)a and VEGF-A(165)b) influence VEGFR-2 receptor trafficking and signaling.
  • To elucidate the role of the coreceptor neuropilin-1 (NRP-1) in modulating VEGFR-2 recycling, degradation, and downstream signal output.
  • To understand the general mechanism of coreceptor function in RTK signal modulation.

Main Methods:

  • Cellular stimulation with specific VEGF-A isoforms (VEGF-A(165)a and VEGF-A(165)b).
  • Analysis of VEGFR-2 trafficking pathways using Rab5, Rab4, Rab11, and Rab7 vesicles.
  • Investigation of NRP-1's role by deleting its GIPC (synectin) binding motif.
  • Assessment of VEGFR-2 dephosphorylation and signal output.
  • Comparative analysis of Epidermal Growth Factor Receptor (EGFR) trafficking.

Main Results:

  • VEGF-A(165)a, binding NRP-1, promoted sequential VEGFR-2 recycling via Rab5, Rab4, and Rab11 vesicles, with dephosphorylation occurring between Rab4 and Rab11.
  • VEGF-A(165)b, not binding NRP-1, caused VEGFR-2 to bypass Rab11 and enter the Rab7 degradative pathway.
  • Deletion of the NRP-1 GIPC binding motif disrupted VEGFR-2 transit through Rab11 vesicles and attenuated signaling.
  • EGFR trafficking through Rab11 vesicles occurred independently of known coreceptors, indicating specificity for VEGFR-2.

Conclusions:

  • Neuropilin-1 plays a specific and critical role in directing VEGFR-2 recycling and modulating its signaling output.
  • VEGF-A isoforms differentially control VEGFR-2 fate by engaging or not engaging NRP-1.
  • Coreceptor engagement provides a general mechanism for fine-tuning RTK signal output.

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