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Review
. 2012 Apr;24(2):188-93.
doi: 10.1016/j.ceb.2012.02.002. Epub 2012 Feb 25.

VEGF signaling inside vascular endothelial cells and beyond

Anne Eichmann  1 , Michael Simons
Affiliations
Review

VEGF signaling inside vascular endothelial cells and beyond

Anne Eichmann et al. Curr Opin Cell Biol. 2012 Apr.

Abstract

Vascular endothelial growth factor-A (VEGF-A) has long been recognized as the key regulator of vascular development and function in health and disease. VEGF is a secreted polypeptide that binds to transmembrane tyrosine kinase VEGF receptors on the plasma membrane, inducing their dimerization, activation and assembly of a membrane-proximal signaling complex. Recent studies have revealed that many key events of VEGFR signaling occur inside the endothelial cell and are regulated by endosomal receptor trafficking. Plasma membrane VEGFR interacting molecules, including vascular guidance receptors Neuropilins and Ephrins also regulate VEGFR endocytosis and trafficking. VEGF signaling is increasingly recognized for its roles outside of the vascular system, notably during neural development, and blood vessels regulate epithelial branching morphogenesis. We review here recent advances in our understanding of VEGF signaling and its biological roles.

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Figures

Figure 1
Figure 1
VEGF binding to VEGFR2, located in close proximity to thrombospondin-2 receptor CD47, promotes VEGFR2 dimerization and activation (phosphorylation of Y1054 and Y1059). At the same time VEGF binding to Nrp1 promotes endocytosis of the VEGFR2/Nrp1 complex, perhaps via Ephrin-B2. Newly endocytosed VEGFR2 in Rab5 endosomes is subject to dephosphorylation of Y1175 site by PTP1b. Trafficking of this endosomes in a synectin/myosin-VI-dependent manner away from the dephosphorylation zone results in full activation of ERK signaling. In addition, a proteolytic cleavage event may take place, releasing the cytoplasmic VEGFR2 dimer.
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