The human KDR/VEGFR2 gene was cloned in 1991 and mapped in 1992 (Terman BI et al., 1991, Terman BI et al., 1992). The human gene (Kdr/VEGFR2) maps to human chromosome 4. The mouse gene (Kdr/Vegfr2/Flk-1) was cloned in 1991(Matthews W et al., 1991). The mouse gene (Flk-1/Vegfr2) is located on mouse chromosome 5.

In humans, the KDR gene consists of 30 exons, spanning 47,337 bp of DNA on the reverse strand of Chromosome 4. Exon 1 contains 5 UTR and exon 30 contains 3 UTR. All 30 exons contain translated sequence. Three splice variants have been reported in Ensembl. Alternative splicing results in partial retention of intron 13 and an alternative stop codon, encoding a unique C-terminal sequence. Transcription factors regulating Vegfr2 expressing include ETS1 and ETS2 (Elvert G et al., 2003, Kappel A et al., 2000), EPAS1 (hypoxia inducible factor 2 alpha) (Elvert G et al., 2003), ETV2 (ER71/etsrp) (Lee D et al., 2008), and OVOL2 (Kim JY et al., 2014).

The canonical form of VEGFR2 comprises 1356 amino acids in humans and 1345 in mice. VEGFR2 is translated into a 150 kDa protein. Glycosylation of the extracellular domain results in the mature form at the cell surface which migrates at 230 kDa via western blot.
VEGFR2 is composed of three domains: an extracellular domain, transmembrane domain, and a cytosolic domain. The extracellular domain (including N-terminus) is composed of a signal peptide (aa: 1-20) and seven Ig-like subdomains (aa: 20-764). The second and third Ig-like subdomains (aa: 141-207, 224-320) facilitate binding of the principal VEGFR2 ligand, VEGFA (Fug G et al., 1998, Shinkai A et al., 1998). This is followed by a single-pass type I transmembrane domain (aa: 765-785).
The intracellular region (aa: 786-1356) consists of a juxtamembrane domain (JMD) and kinase domain. Biochemical analyses by Solowiej et al. (2009) determined that the JMD promotes autophosphorylation of the kinase domain, which is preceded by phosphorylation of the JMD residue, Y801(Solowiej J et al., 2009). Replacing the VEGFR2 JMD with the VEGFR1 JMD reduces the kinase activity of VEGFR2 in vitro. Conversely, replacing the VEGFR1 JMD with the VEGFR2 JMD increases the kinase activity of VEGFR1(Gille H et al., 2000). These data suggest that the higher kinase activity of VEGFR2 relative to VEGFR1 may be partially explained by differences in the JMD.
The kinase domain (KD; aa: 834-1162) is split by a 70 amino acid insert (aa: 930-1000). Phosphorylation of the KD activation loop residues Y1054 and Y1059 is required for kinase activity(Kendall RL et al., 1999). Additional phosphorylation sites in the intracellular domain facilitate specific interactions of between VEGFR2 and signaling mediators, including PLC gamma, SHB, SCK, SHCA, GRB2, son of sevenless (SOS), and NCK. For further review, see S. Koch and L. Claesson-Welsh, 2012, and Claesson-Welsh and Welsh, 2013 (Claesson-Welsh L et al., 2013, Koch S et al., 2012).
Co-receptors:
Integrins, neuropilin-1, and CD146 promote VEGFR2 activation, and mediate VEGFR2 activities, including endothelial cell migration, permeability, and angiogenesis. For more information, see Table 1 and Koch and Claesson-Welsh, 2012.
Alternative Isoforms:
In 2009, Albuquerque et al. discovered that alternative splicing produces a soluble form of VEGFR2, present in mouse and human cornea (Albuquerque RJ et al., 2009). This isoform results from inclusion of the intron following exon 13 and results in a truncated product which migrates at 75 kDa via western blot. This isoform contains only the extracellular domain of VEGFR2 and a unique C-terminal sequence. Characterization of sVEGFR2 revealed that it may play a role as an endogenous inhibitor of lymphoangiogenesis via antagonizing VEGF-C/VEGFR3 signaling (Albuquerque RJ et al., 2009).
Ligands:
VEGF-A (Terman BI et al., 1992), VEGF-C (Joukov V et al., 1996), VEGF-D (Achen MG et al., 1998), and VEGF-E (M Meyer et al., 1999, Ogawa S et al., 1998). VEGF-A is the primary endogenous ligand activating VEGFR2 signaling, while VEGF-C and VEGF-D signal mostly through VEGFR3. VEGF-E is encoded by the Orf virus and activates VEGFR2 similarly to VEGF-A. Unlike VEGF-A, however, VEGF-E is a VEGFR2-exclusive ligand.

VEGFR2 is the principal VEGF receptor expressed on blood endothelial cells. Vegfr2-null mice die at E8.5 due to inadequate development of endothelial and hematopoietic cells(Shalaby F et al., 1995). Vegfr2 expression levels peak during embryonic angiogenesis and vasculogenesis(Millauer B et al., 1993, Oelrichs RB et al., 1993). In adults, VEGFR2 is expressed prominently on vascular endothelial cells, where its expression is, in part, regulated by fibroblast growth factor signaling(Michael S. Pepper et al., 1998, Murakami M et al., 2011). Expression is also observed on hematopoietic stem cells and megakaryocytes(Casella I et al., 2003, Katoh O et al., 1995, Larrivée B et al., 2003).

Full length VEGFR2 is localized on the plasma membrane and is internalized in a VEGF binding-dependent manner(Koch S et al., 2012, Waltenberger J et al., 1994). Soluble VEGFR2 is secreted from the cell.

VEGFR2 is the premier receptor mediating VEGF-A activity on endothelial cells, where it functions to enhance proliferation, migration, and survival(Gerber HP et al., 1998, Jia H et al., 2004, Terman BI et al., 1992, Waltenberger J et al., 1994). Vegfr2 also promotes the survival of hematopoietic stem cells(Larrivée B et al., 2003).
VEGFR2 is the principal VEGF receptor involved in vascular angiogenesis and the regulation of vascular permeability(Kowanetz M et al., 2006, Terman BI et al., 1992). VEGFR2 activity on vascular endothelial cells in tumors promotes tumor angiogenesis(K. H. Plate et al., 1993, Millauer B et al., 1994). For the effects of VEGFR2 signaling on different cell types, see Table 2.
VEGF Signaling Inhibitors:
Strategies employed to target VEGF signaling are multifocal, consisting of monoclonal antibodies for both the ligands and VEGFRs, recombinant VEGFR extracellular domain fusion proteins (Table 3), and small molecule receptor tyrosine kinase inhibitors (Table 4)

Increased VEGFR2 copy number has been identified in breast(Johansson I et al., 2012), non-small cell lung cancer (Yang F et al., 2011), and neurological malignancies (Blom T et al., 2010, Puputti M et al., 2006). Missense mutations have been identified in hemangioma, leading to constitutive activation of VEGFR2 (Antonescu CR et al., 2009, Jinnin M et al., 2008, Walter JW et al., 2002). Wang et al., 2007, identified that polymorphisms in the VEGFR2 were associated with coronary heart disease(Wang Y et al., 2007) (Table 5).
Glubb et al., 2011, characterized the significance of selected single nucleotide polymorphisms on VEGFR2 function and expression (Table 6). Of particular note, Glubb et al., 2011, identified that a SNP that results in the amino acid change Q472H, which was associated with increased VEGFR2 activity, and was correlated with increased microvessel density in non-small cell lung cancer patients (Glubb DM et al., 2011) (Table 6).