Vascular endothelial growth factor (VEGF) signaling transduction plays a major role in physiological and pathological angiogenesis, such as cancer. Five VEGF, VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PlGF, also known as PGF), bind with different affinities to three VEGF receptor tyrosine kinases (VEGFR) and two NRP coreceptors causing them to dimerize. VEGF belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure.
All members of VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, initiating homo- and heterodimer formation and become activated through transphosphorylation. Following the phosphorylation, series of signaling cascades that promote endothelial cell growth, migration, and differentiation occur.
VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1). VEGFR1 may regulate endothelial cells via cross-talk with VEGFR2. VEGFR2 is known to transduce the full range of VEGF responses in endothelial cells, regulating endothelial survival, proliferation, migration and formation of the vascular tube. The last two VEGFs, VEGF-C and VEGF-D, which are ligands for a third receptor (VEGFR-3/Flt4), mainly regulate lymphangiogenesis.
In addition to binding to VEGFRs, VEGF binds to receptor complexes consisting of both neuropilins and VEGFRs. This receptor complex has increased VEGF signalling activity in endothelial cells. Neuropilin-1 (NRP-1) and Neuropilin-2 (NRP-2) are pleitrophic receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes (Figure 1).
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