Disease relevance of KDR

• A phage epitope library was screened by affinity for membrane-expressed KDR or for an anti-VEGF neutralizing monoclonal antibody [1].
• Earlier, we showed that in some leukemias, a VEGF/KDR autocrine loop is essential for cell survival, whereas here we identified the molecular correlates for such an effect [2].
• Furthermore, a highly significant correlation was observed between Ets-1 and Flt-1 (but not KDR) expression in ECs of the glioma microvasculature [3].
• Our prior studies show that multiple myeloma (MM) cell lines and patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor (VEGFR) Flt-1 but not Flk-1/KDR [4].
• A significant increase was observed in flt-1 (P < 0.001), KDR (P = 0.02), and flt-4 (P = 0.01) but not VEGF-B (P = 0.82) or VEGF-C (P = 0.52) expression in clear cell compared with chromophil (papillary) carcinomas [5].

High impact information on KDR

• In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1 [6].
• Conversely, inhibition of VEGF165 binding to neuropilin-1 inhibits its binding to KDR and its mitogenic activity for endothelial cells [7].
• A 280 kd receptor displays high affinity for both TGF-beta 1 and TGF-beta 2 [8].
• A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2 [9].
• Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps [10].

Chemical compound and disease context of KDR

• Transient transfection with antisense oligonucleotides targeted on the translation initiation codon of KDR abolished its tyrosine phosphorylation and mitogenic response of neonatal hemangioma cells to VEGF, confirming the existence of an autocrine loop of proliferation [11].
• The soluble isoform of VEGF is a dimeric glycoprotein of 36-46 kDa, induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine-kinase receptors: VEGF-1 (flt-1) and VEGF-2 (KDR/flk1) [12].
• Blockade of VEGFR2 signaling using DC101 anti-VEGFR2 monoclonal antibody enhanced doxorubicin chemoresponse; this combined biochemotherapy inhibited tumor growth and decreased pulmonary metastases without overt toxicity [13].
• PURPOSE: To assess the activity of the antiangiogenic agent and VEGFR2 inhibitor SU5416 in hormone-refractory prostate cancer [14].
• Pituitary Tumor Transforming Gene (PTTG) Stimulates Thyroid Cell Proliferation via a Vascular Endothelial Growth Factor/Kinase Insert Domain Receptor/Inhibitor of DNA Binding-3 Autocrine Pathway [15].

Biological context of KDR

• When coexpressed in cells with KDR, neuropilin-1 enhances the binding of VEGF165 to KDR and VEGF165-mediated chemotaxis [7].
• We demonstrate in 2 cell lines and 5 FLT-4(+) leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios [16].
• In addition, although VEGF receptors were higher in tumors than normal kidney, there was a significant up-regulation of only flt-1 (P = 0.003) but not KDR (P = 0.12) or flt-4 (P = 0.09) [5].
• We demonstrated previously that antagonistic antibodies to KDR specifically inhibited VEGF-stimulated receptor activation, cell migration, and endothelial cell mitogenesis [17].
• Although considerable experimental evidence links KDR activation to endothelial cell mitogenesis, there is still significant uncertainty concerning the role of individual VEGF receptors for other biological effects such as vascular permeability [18].

Anatomical context of KDR

• We have investigated the expression of Flt1 and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo) lineage [19].
• By interfering with the VEGF-KDR interaction, the peptide K237 inhibited proliferation of cultured primary human umbilical vein endothelial cells induced by recombinant human VEGF(165) in a dose-dependent and cell type-specific manner [20].
• Our results indicate that RPE secretes VEGF toward its basal side where its receptor KDR is located on the adjacent CC endothelium, suggesting a role of VEGF in a paracrine relation, possibly in cooperation with flt-4 and its ligand [21].
• A functional product of the KDR gene encoding a cognate VEGF receptor was also expressed by these stromal cells [11].
• Dorsal root ganglion (DRG) neurons expressed high levels of NP-1 mRNA and protein, much lower levels of KDR, and no detectable Flt-1 [22].

Associations of KDR with chemical compounds

• The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells [23].
• Like VEGF, FG-4095 and DMOG increased angiogenesis in vitro, both in 95% and 21% O2, an effect that could be blocked through either Flt-1 or KDR [24].
• As was the case for native KDR, (125)I-VEGF(165) binding to the mutant receptors was dependent upon cell surface heparan sulfate proteoglycans, and (125)I-VEGF(121) bound with an affinity equal to that of (125)I-VEGF(165) to the native and mutant receptors [25].
• Furthermore, the mutation of tyrosine 1059 to phenylanaline results in the complete loss of KDR/EGDR-mediated intracellular Ca(2+) mobilization and MAPK phosphorylation, but the mutation of tyrosine 951 to phenylanaline did not affect these events [26].
• In conclusion, high glucose causes an uncoupling of VEGF with NO, which enhances endothelial cell proliferation via activation of the KDR-ERK1/2 pathway [27].

Physical interactions of KDR

• Of the synthetic peptides corresponding to selected clones tested to determine their inhibitory activity, ATWLPPR completely abolished VEGF binding to cell-displayed KDR [1].
• Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration [28].
• Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition [29].
• Furthermore, we also observed that dynamin-2 coimmunoprecipitates with KDR and is required for EC signaling/survival [30].
• We demonstrated that TFII-I binds to both the Inr and to three regulatory E boxes in the human VEGFR-2 promoter [31].

Enzymatic interactions of KDR

• With regard to gene expression, incubation with MG63-CM abolished endogenous VEGF mRNA and protein but induced a clear-cut increase in VEGFR2 mRNA expression in EC [32].
• Wound assays reveal that IQGAP1 and phosphorylated VEGFR2 accumulate and colocalize at the leading edge in actively migrating ECs [33].
• Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells [34].

Co-localisations of KDR

• VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes [35].

Regulatory relationships of KDR

• CONCLUSIONS: Cholangiocytes secrete VEGF and express VEGFR-2 and VEGFR-3, all of which are amplified in BDL cholangiocytes [36].
• All the myeloma cell lines expressed VEGFR1 and three of the cell lines expressed VEGFR2 [37].
• On the endothelium, NRP is expressed together with KDR, a VEGF receptor tyrosine kinase [38].
• Further, the VEGFR-2-mediated signaling transduction pathway may be involved in LPA-induced EOC invasion and migration by regulating the secretion and activation of MMP-2 and uPA [39].
• Taken together, our data demonstrated that TNF induces transactivation between Etk and VEGFR2, and Etk directly activates PI3K-Akt angiogenic signaling independent of VEGF-induced VEGFR2-PI3K-Akt signaling pathway [40].

Other interactions of KDR

• VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively [41].
• We conclude that TNF-alpha downregulates expression of both VEGF receptors in human endothelial cells and that this effect is transcriptional (at least for KDR/flk-1) [42].
• Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1 [43].
• No significant association was demonstrated between VEGF-B, VEGF-C, flt-1, KDR, and flt-4 with patient sex, patient age, or tumor size (P > 0.05) [5].
• CDB-2914 treatment alone decreased VEGFR-1, VEGFR-2 and ADMR contents in cultured leiomyoma cells but not in normal myometrial cells [44].
• VEGFR2 up-regulation had no effect on VEGF-induced cell proliferation, but significantly enhanced EPC migration and pseudotubes formation dependent on integrin alpha(6) subunit overexpression [45].

Analytical, diagnostic and therapeutic context of KDR

• KDR is a major positive signal transducer for angiogenesis through its strong tyrosine kinase activity [46].
• Two-hybrid cloning and immunoprecipitation from human umbilical vein endothelial cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase Cgamma (PLCgamma) [47].
• Expression of flt-1 and KDR/flk-1 mRNA in eosinophils was demonstrated in reverse transcriptase-polymerase chain reaction, and receptor expression was investigated by fluorescence-activated cell sorting analysis [48].
• Epitope mapping studies demonstrated that all neutralizing human antibodies bound the epitope(s) located within the first 3 N-terminal immunoglobulin-like domains of KDR, the same region that encompasses the binding site of VEGF [49].
• We developed a cell culture model using porcine aortic endothelial cells overexpressing KDR for testing the efficiency of anti-KDR intrabodies [50].

References