Source:
Sigma-RBI Handbook of Receptor Classification and Signal Transduction, Sigma-RBI (2006)
URL:
http://www.sigmaaldrich.com/Area_of_Interest/Life_Science/Cell_Signaling/Sigma_RBI_Handbook2.html
Abstract:
The vascular endothelial growth factor receptor (VEGFR) family comprises in humans three endothelial cell (EC) specific tyrosine kinase receptors (VEGFR-1, VEGFR-2 and VEGFR-3). VEGFRs are the major direct mediators of proliferation of blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs). Individual VEGFRs become activated by different subsets of the vascular endothelial growth factor (VEGF) family.
VEGFR-2 is the central mediator of the formation (vasculogenesis), growth (angiogenesis) and maintenance of blood vessels. It is also a marker for the common precursors of blood and endothelial cells (hemangioblasts). VEGFR-2 continues to be expressed in the differentiated endothelial lineage, but is downregulated by hematopoietic cells. The importance of VEGFR-2 for vasculogenesis and hematopoiesis is seen in knock-out mice which fail to develop both blood islands and blood vessels.
In contrast to VEGFR-2, VEGFR-1 has a more limited scope of action. In fact, it was thought that all functions of VEGF except for its chemoattractive role for monocytes were mediated exclusively by VEGFR-2. VEGFR-2 selective VEGF mutants or viral homologues are fully active EC mitogens, whereas VEGF family members or mutants which bind only to VEGFR-1 largely lack the ability to promote EC growth. Mice lacking the tyrosine kinase domain of VEGFR-1 are normal; only the VEGF-induced migration of their macrophages is reduced in vitro. However, complete ablation of VEGFR-1 results in embryonic lethality because increased endothelial precursor proliferation leads to a disorganized vasculature. Based on these results, VEGFR-1 was regarded as a decoy receptor with negligible signaling properties. However, recent reports indicate that there is a more complex interplay between VEGFR-1 and VEGFR-2 including heterodimerization in pathological angiogenesis.
In early embryogenesis all three VEGFRs are expressed in endothelial cells. Concomitantly with the development of the lymphatic vessels VEGFR-3 becomes restricted to the lymphatic endothelium. While the ligand binding characteristics of VEGFR-1 and VEGFR-2 are conserved between humans and mice, VEGFR-3 shows more interspecies variability: in humans both VEGFR-3 ligands (VEGF-C and VEGF-D) are also capable of activating VEGFR-2 and are therefore potentially angiogenic, whereas mouse VEGF-D can only activate VEGFR-3. Moreover, in higher primates a retroviral insertion into the VEGFR-3 gene has led to the emergence of two splice isoforms, which differ in their signaling properties.
Of the seven extracellular Ig-like domains of VEGFRs, the three N-terminal ones are responsible for ligand binding; further deletion of at least one domain is tolerated without significant loss of affinity. The functions of the remaining extracellular domains are less well defined; however a duplication event within these domains marks the evolutionary segregation between the VEGF and the PDGF/CSF-1/SCF receptor families.
Due to the central role of endothelial cells in both cardiovascular and neoplastic disease, VEGFRs have been used as targets for both pro- and antiangiogenic therapy. Proangiogenic therapy has mostly employed various VEGFs or modified versions thereof to stimulate VEGFR signaling. Antiangiogenic therapy can target VEGFRs at three different levels: 1. Soluble forms of the receptor ("ligand traps") can sequester receptor agonists (a method that nature itself uses to downregulate VEGF signaling), 2. Molecules (antibodies, aptamers, small peptides, dominant negative receptors, synthetic compounds) can block agonist binding or receptor dimerization, 3. Specific inhibitors can block the tyrosine kinase activity (ATP analogs) or critical transphosphorylation sites (small peptides, nonphosphorylatable peptide analogs). While angiogenesis can also be suppressed using other targets than VEGFRs, VEGFRs seem to be among the most promising drug targets with several compounds in clinical trials and even one on the market.