VEGF Family Ligands and Receptor Interactions
VEGF (Vascular Endothelial Growth Factor) is a highly conserved genetic pathway that has evolved from simple to complex systems. The early evolutionary role of VEGF in simple invertebrate systems (Drosophila or fruit fly), was to guide the movement and dissemination of blood cells to eliminate dying cells and mount a defensive or inflammatory response to infection and wounds. Over time, the role of VEGF, PDGF (Platelet-Derived Growth Factor-Alpha Polypeptide), and the related family of signaling receptors provided for more complex and diversified cellular functions in vertebrate systems; for example, the more specialized role of blood vessel formation. VEGF signaling is critical to the processes of angiogenesis and tumor growth [1-3]. VEGF is a heparin-binding homodimeric glycoprotein that acts via endothelial-specific receptor tyrosine kinases/VEGFRs (Vascular Endothelial Growth Factor Receptors); VEGFR1 (FLT1), VEGFR2 (KDR/Flk1), and VEGFR3 (FLT4). The VEGF family of growth factors currently contains six other known members, namely PLGF (Placenta Growth Factor), VEGFA, VEGFB, VEGFC, VEGFD, and orf viral VEGF homologs. Besides the VEGFRs, Nrp1 (Neuropilin-1) is also expressed in endothelial cells and functions as an isoform-specific receptor for VEGF. Disruption of the genes encoding either VEGF or any of the receptors of the VEGF family, results in embryonic lethality because of failure of blood vessel development .
VEGF stimulation affects not only endothelial cell signaling but also tumor cells expressing VEGFRs. A number of signal transduction molecules are activated or modified in response to VEGF stimulation in primary endothelial cells. After receptor dimerization and autophosphorylation, signal transduction molecules are activated directly by receptor binding, and the primary targets mainly includes PI3K (Phosphatidylinositde-3 Kinase); PLC-Gamma (Phospholipase-C-Gamma); GRB2 (Growth Factor Receptor-Bound Protein-2); SOS (Son of Sevenless); and the Src homology domain containing SHC proteins. Activation of PI3K results in accumulation of PIP3 (Phosphatidylinositol 3,4,5-trisphosphate) via PIP2 (Phosphatidylinositol-4,5-bisphosphate) degradation, which in turn mediates membrane targeting and phosphorylation of Akt (v-Akt Murine Thymoma Viral Oncogene Homolog)/PKB (Protein Kinase-B) by binding to its pleckstrin homology (PH) domain, Akt enters Akt signaling and regulates endothelial cell survival. These events are also essential for VEGF-induced endothelial cell migration, cell proliferation, and actin reorganization [5-7]. PLC-Gamma may also be activated downstream of the VEGFRs . Phosphorylated PLC-Gamma catalyzes the hydrolysis of PIP2 to generate IP3 (Inositol-1,4,5-trisphosphate) and DAG (Diacylglycerol), which are known to stimulate the release of Ca2+ (Calcium) from internal stores and activate PKC (Protein Kinase-C), respectively. Indeed, increased Ca2+ release in response to VEGF is important for eNOS (Endothelial Nitric Oxide Synthase) activation and regulates short-term production of nitric oxide and prostaglandin (which includes Prostacyclin/PGI2 and PGE2/Prostaglandin-E2) . A major route from the receptors to Ras activation involves direct association of the adaptor protein GRB2 to the receptor and subsequent stimulation of the guanine-nucleotide exchange protein SOS. Another potential route is mediated by the adaptor protein SHC. VEGF stimulates SHC phosphorylation and promotes formation of SHC-GRB2 complexes. This may result in Ras activation, leading to activation of the Raf1 (v-Raf1 Murine Leukemia Viral Oncogene Homolog-1)>MEK (MAPK/ERK Kinase)1/2>ERK (Extracellular Signal-Regulated Kinase)1/2 cascade that is critical for growth stimulation, downstream of most protein tyrosine kinase receptors including activation of the transcription factor, c-Fos . Moreover, VEGF also induces PKC-dependent and Ras-independent induction of the Raf1>MEK1/2>ERK1/2>cPLA2 (Cytosolic Phospholipase-A2) pathway in endothelial cells. These mechanisms ultimately control vasopermeability and angiogenesis . Not only does VEGF play an essential role in the normal development and differentiation of the vascular system, it also plays a key role in pathologic angiogenesis such as tumor Angiogenesis. On the other hand, expressions of the VEGFRs are typically up-regulated in tumor-associated endothelial cells, which is consistent with the prime actions of VEGF as a paracrine factor . The VEGF signaling pathway may, therefore, be an important target for modulating inflammatory response as well as angiogenesis and present novel opportunities for intervening in serious inflammatory or autoimmune diseases.
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