ReviewVascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition
Introduction
Vascular endothelial growth factor (VEGF) represents a family of homodimeric glycoproteins which are critical for the embryonic development of the blood vascular system (vasculogenesis), lymphatic system (lymphangiogenesis) and in the formation of new blood vessels from pre-existing vessels (angiogenesis). In mammals, five different VEGF ligands have been identified and one parapoxvirus-encoded VEGF. These ligands bind, in an overlapping pattern, to three different, but structurally related, VEGF-receptor (VEGFR) tyrosine kinases. VEGFR-1 is critical for haematopoietic cell development, VEGFR-2 is critical for vascular endothelial cell development and VEGFR-3 critical for lymphatic endothelial cell development.
As our understanding of the role of VEGFs and VEGFRs in both physiological vascular development and pathological diseases, such as tumour angiogenesis, has grown over the last decade, a number of researchers have identified the signalling pathways downstream of the VEGF receptors. Selective activation of VEGFR-1 and VEGFR-2, coupled with gene silencing, has revealed that VEGFR-2 is the principal receptor transmitting VEGF signals in the vascular endothelium. This review will focus on our current understanding of VEGFR-2 signalling in endothelial cells and the clinical development of inhibitors of VEGFR-2 function.
Section snippets
The VEGF ligands
In mammals, the VEGF family consists of five members, VEGF-A, VEGF-B, VEGF-C, VEGF-D and placenta growth factor (PLGF). Structurally related proteins include parapoxvirus Orf VEGF, denoted VEGF-E [1], and snake venom VEGFs, denoted VEGF-F [2], [3]. VEGF-A was first described in 1983, by Senger and coworkers, as a tumour-secreted vascular-permeability factor (VPF) [4]. In 1989, Ferrara and Henzel reported the isolation and amino-acid sequence of an endothelial cell mitogen they named VEGF [5].
The VEGF receptors
VEGFs signal through cell surface receptor tyrosine kinases (Fig. 2). VEGFR-1 (Flt-1) is expressed on haematopoietic stem cells, monocytes, macrophages and vascular endothelial cells. VEGFR-2 (Flk-1/KDR) is expressed on vascular endothelial cells and lymphatic endothelial cells, whilst VEGFR-3, (Flt-4) expression is restricted to lymphatic endothelial cells. An alternatively spliced soluble VEGFR-1 variant (sVEGFR-1) is also expressed (for a review of VEGFR-1 and VEGFR-3, the reader is referred
VEGFR-2 structure
VEGFR-2 (kinase-insert domain receptor (KDR)/foetal liver kinase (Flk)-1) is a type III transmembrane kinase receptor, first isolated in 1991 by Terman and coworkers [22]. The human VEGFR-2 gene, located on chromosomes 4q11–q12, encodes a full-length receptor of 1356 amino acids [23]. It consists of an extracellular region composed of seven immunoglobulin (Ig)-like domains, a short transmembrane domain, and an intracellular region containing a tyrosine kinase domain, split by a 70-amino-acid
VEGFR-2 function
In murine embryogenesis, expression of VEGFR-2/Flk-1 is first detected at E7.0 in mesodermal blood island progenitors. Slightly later the gene is expressed in endothelial cell precursors and developing endothelial cells [41], [42], [43]. The critical role of VEGFR-2 in vascular development is highlighted by the fact that VEGFR-2−/− mice die at E8.5-9.5 due to defective development of blood islands, endothelial cells and haematopoietic cells [44]. In the adult, VEGFR-2 is expressed mostly on
VEGFR-2 intracellular signalling
A number of studies have shown that VEGFR-2 is the principal mediator of several physiological and pathological effects of VEGF-A on endothelial cells. These include proliferation, migration, survival and permeability. The intracellular signalling pathways mediating these effects downstream of VEGFR-2 activation are shown schematically in Fig. 4.
VEGFR-2 regulated gene expression
A number of studies have utilised techniques such as cDNA microarrays to identify genes which are upregulated in endothelial cells, following stimulation with VEGF [82], [83], [84], [85], [86]. Whilst a number of genes with known roles in angiogenesis were identified, such as Cox-2, a number of novel genes have also been identified, such as Down syndrome critical region-1 (DSCR-1). DSCR-1 was identified as the most highly upregulated gene in one study in VEGF stimulated endothelial cells [83],
VEGFR-2 signalling in disease and therapeutic inhibition
Angiogenesis plays a role in a number of pathological conditions, with VEGFR-2 signalling implicated in both tumour angiogenesis, and diabetic retinopathy [91]. Angiogenesis is crucial for tumour development as cancer cells have a relatively high metabolic demand for oxygen and nutrients to continue growing. Furthermore, the capillary and vascular network allows tumours to metastasise and spread to other sites in the body. Tumour vasculature is highly disorganised, and tumour blood flow is
Conclusions and perspectives
Research over the last decade has revealed the complexity of VEGFR signalling. Three different, but related, receptor tyrosine kinases regulate different aspects of vascular function. VEGFR-2 signalling has been the most intensively studied, as this receptor mediates the effects of VEGF-A on the vascular endothelium. This research has revealed a complex signalling mechanism regulating different aspects of physiological, and pathological angiogenesis. The development of anti-angiogenic drugs,
Acknowledgements
The authors are supported by grants from the Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council/AstraZeneca (BBSRC/AZ CASE award), Cancer Research Wales (CRW) and North West Cancer Research Fund (NWCRF).
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