Affinage

KDR

Vascular endothelial growth factor receptor 2 · UniProt P35968

Length
1356 aa
Mass
151.5 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDR (VEGFR-2) is a receptor tyrosine kinase that serves as the principal endothelial transducer of VEGF signals driving vascular proliferation, migration, and angiogenesis (PMID:30283071, PMID:10953026). It exists as pre-formed unliganded dimers that are basally phosphorylated, with ligand binding to extracellular domains 2–3 inducing a transmembrane-domain conformational change that boosts kinase activation; energetically unfavorable homotypic contacts in domains 4–7 enforce monomer re-orientation and suppress ligand-independent firing, and the pathogenic C482R mutant bypasses this restraint by mimicking the ligand-bound dimer (PMID:27052508, PMID:22207738). Activation requires intracellular tyrosines (notably Y799/Y1173 for growth and PI3K activation, and Y1212 for autophosphorylation) and is potentiated by ligand-independent lysine methylation at Lys1041 adjacent to the activation loop, which enhances tyrosine phosphorylation and is required for angiogenesis and tumor growth in vivo (PMID:12814952, PMID:24300896). Productive signaling proceeds through PI3K/Akt, MAPK/ERK, and PLC/PKC arms to control endothelial proliferation, survival, and cell-cycle progression (PMID:18719373, PMID:12814952). Receptor output is shaped by an extensive set of partners: CD146, EMMPRIN/CD147, and neuropilins act as coreceptors that enhance VEGFR-2 phosphorylation and angiogenic responses (PMID:22718841, PMID:25825981, PMID:16621967, PMID:17185751); heterodimers with VEGFR-1 yield migration and vasorelaxation without proliferation (PMID:22828632); and CLP24 and CLEC14A balance VEGFR-2 against VEGFR-3 in lymphatic and vascular development (PMID:20439428, PMID:27991863). Receptor abundance and surface levels are regulated transcriptionally by G13/RhoA/NF-κB and by promoter DNA methylation, by the chaperone PDCL3 against misfolding, by ER E3 ligase RNF121-mediated ubiquitination, and by PKC/serine-1188/1191-dependent down-regulation and agonist-induced internalization (PMID:23664862, PMID:22251800, PMID:26059764, PMID:26602861, PMID:15673613, PMID:17382929). Beyond angiogenesis, VEGFR-2 mediates Sema3E-driven axonal growth in neurons via a PlexinD1/NRP1 complex independent of VEGF ligands (PMID:20434998), and a germline C482R variant accounts for a substantial fraction of serum soluble VEGFR-2 variance (PMID:25411163).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established that VEGFR-2 is a functional, ligand-activated signaling receptor on non-endothelial (leukemic) cells and a valid anti-cancer target, extending its role beyond endothelium.

    Evidence VEGF165 phosphorylation, proliferation/migration assays, neutralizing anti-KDR mAb, and leukemia xenografts; plus VEGF-C/VEGFR-2 epistasis in mouse embryos

    PMID:10953026 PMID:11090062

    Open questions at the time
    • Did not resolve which downstream pathway dominates autocrine proliferation
    • Cross-talk with VEGFR-3 in normal vasculogenesis only inferred from deficient embryos
  2. 2003 Medium

    Mapped intracellular tyrosines required for VEGFR-2-specific endothelial growth and PI3K activation, distinguishing its signaling from VEGFR-1.

    Evidence Chimeric CSF-1R/VEGFR-2 receptors and site-directed mutagenesis of Y799, Y1173, Y1212 with endothelial functional and PI3K assays

    PMID:12814952

    Open questions at the time
    • Specific adaptors docking at each phosphotyrosine not identified
    • Single lab, single publication
  3. 2005 High

    Defined the carboxyl-tail and PKC-dependent machinery that down-regulates the receptor, showing c-Cbl phosphorylates but does not ubiquitinate VEGFR-2.

    Evidence Progressive deletion mutants, S1188/S1191 mutagenesis, and pharmacological PKC inhibition with down-regulation assays

    PMID:15673613

    Open questions at the time
    • Identity of the responsible non-classical PKC isoform not pinned down
    • Kinase phosphorylating S1188/S1191 not established
  4. 2006 Medium

    Showed neuropilins act as coreceptors that raise VEGFR-2 phosphorylation threshold and ligand affinity, including for non-neuropilin-binding VEGF121, via pre-formed complexes.

    Evidence Co-IP, NRP siRNA/overexpression, VEGF binding-affinity and phosphorylation assays, VEGF165 neuropilin-binding mutant

    PMID:16621967 PMID:17185751

    Open questions at the time
    • Structural basis of NRP1/2-VEGFR-2 coupling unresolved
    • Whether NRP1 vs NRP2 select different downstream outputs not addressed
  5. 2007 Medium

    Linked VEGFR-2 internalization to nuclear trafficking dependent on FLT-1, PI3K/AKT, and receptor phosphorylation as a requirement for endothelial monolayer repair.

    Evidence KDR tyrosine deletion mutants, PI3K inhibition, FLT-1 antibody blockade, nuclear fractionation, in vitro wound healing

    PMID:17382929

    Open questions at the time
    • Function of nuclear KDR not defined
    • Trafficking route and cargo machinery only partially characterized
  6. 2010 High

    Revealed a VEGF-independent neuronal role: VEGFR-2 transduces Sema3E via a PlexinD1/NRP1 complex to drive axonal growth through PI3K/Akt.

    Evidence Mouse neuronal expression analysis, Co-IP of VEGFR-2/PlexinD1/NRP1, Sema3E-induced phosphorylation, and axonal growth assays; plus CLP24 interaction and Clp24 KO genetic epistasis for lymphatic development

    PMID:20434998 PMID:20439428

    Open questions at the time
    • How Sema3E activates VEGFR-2 kinase without VEGF is mechanistically unclear
    • CLP24 effect on CREB signaling not connected to canonical VEGFR-2 outputs
  7. 2011 High

    Established the activation mechanism: pre-formed basally phosphorylated dimers activated by a transmembrane conformational change, restrained by unfavorable D4–7 contacts, with C482R mimicking the active conformation.

    Evidence Quantitative FRET, phosphorylation analysis, mutagenesis; ITC, SAXS, and crystal structures of VEGF-A/E with domains D23

    PMID:22207738 PMID:27052508

    Open questions at the time
    • Full-length receptor structure in membrane not solved
    • Exact residues mediating D4–7 homotypic contacts not enumerated
  8. 2012 High

    Distinguished VEGFR-1/VEGFR-2 heterodimer outputs (migration, vasorelaxation, no proliferation) from homodimers, and identified CD146 as a required coreceptor for VEGFR-2 activation.

    Evidence Bispecific synthetic ligand with functional readouts; CD146 Co-IP/pulldown, siRNA, antibody, and endothelial-specific KO mice

    PMID:22718841 PMID:22828632

    Open questions at the time
    • Stoichiometry and physiological abundance of heterodimers in vivo unknown
    • How CD146 alters receptor conformation not defined
  9. 2013 High

    Showed Lys1041 methylation is a constitutive, ligand-independent enhancer of kinase activity required for angiogenesis, and that G13/RhoA/NF-κB transcriptionally sets VEGFR-2 levels for angiogenic responsiveness; VEGFR-2 cooperates with VEGFR-3 in lymphangiogenesis.

    Evidence MS site mapping, K1041 mutagenesis, methyltransferase inhibition with zebrafish/mouse models; endothelial G13 conditional KO with NF-κB promoter site and rescue; receptor-selective antibody double-blockade in lymphatics

    PMID:17210781 PMID:23664862 PMID:24300896

    Open questions at the time
    • Methyltransferase responsible for K1041 not identified
    • How methylation alters activation-loop dynamics structurally unresolved
  10. 2014 Medium

    Characterized post-translational and direct-binding regulators of VEGFR-2 activity and linked the C482R germline variant to circulating soluble VEGFR-2 levels.

    Evidence GABARBP Co-IP and PI3K-pathway/functional assays; GWAS of sVEGFR-2 with pazopanib pharmacodynamics

    PMID:24686084 PMID:25411163

    Open questions at the time
    • GABARBP physiological context single-lab only
    • rs34231037 mechanism is association-only in the GWAS itself
  11. 2015 Medium

    Defined biosynthetic quality control of VEGFR-2 through the chaperone PDCL3 and ER E3 ligase RNF121, plus EMMPRIN/CD147 as an extracellular coreceptor.

    Evidence Co-IP, siRNA/shRNA and overexpression, ubiquitination assays, RING-domain mutants, and in vivo angiogenesis; EMMPRIN docking and mutagenesis

    PMID:25825981 PMID:26059764 PMID:26602861

    Open questions at the time
    • Interplay between RNF121 ubiquitination and PDCL3 folding not integrated
    • Single-lab observations for each regulator
  12. 2017 Medium

    Connected receptor trafficking and signaling to mechanical and metabolic cues: RCAN1.4 and matrix stiffness govern internalization and polarity, while autophagy/ROS activates VEGFR-2 independently of VEGF.

    Evidence siRNA/adenoviral RCAN1.4 with zebrafish; tunable hydrogels and ROCK inhibition; glioma-stem-cell autophagy modulation with ATG5 knockdown and ROS measurement

    PMID:28271280 PMID:28812437 PMID:29531793

    Open questions at the time
    • Direct molecular link between ROS and KDR phosphorylation not defined
    • Single-lab, context-specific models
  13. 2018 High

    Demonstrated that endothelial Vegfr2 gene dosage, not hematopoietic expression, is the critical determinant of tumor angiogenesis and growth.

    Evidence Vegfr2 heterozygous and cell-type-specific conditional KO mice across three independent tumor models

    PMID:30283071

    Open questions at the time
    • Threshold of receptor abundance defining angiogenic competence not quantified
    • Why endothelial Fgfr1/2 deletion gave no synergy unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The enzymes and signals that set ligand-independent regulatory marks (K1041 methyltransferase, S1188/S1191 kinase) and how coreceptor binding and mechanical/metabolic inputs are integrated into distinct downstream programs remain open.
  • No enzyme identified for K1041 methylation
  • No unifying model linking coreceptors, dimer state, and pathway selection
  • Function of nuclear-localized VEGFR-2 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
BSGCD146FLT1NRP1NRP2PDCL3PLXND1RNF121
Complex memberships
VEGFR-2/PlexinD1/NRP1 complexVEGFR-2/VEGFR-1 heterodimer

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 VEGFR-2 forms pre-formed dimers in the absence of ligand when expressed at physiological levels, and these unliganded dimers are phosphorylated. Ligand binding induces a conformational change in the transmembrane domain, resulting in increased kinase domain phosphorylation. The pathogenic C482R VEGFR-2 mutant (linked to infantile hemangioma) promotes ligand-independent signaling by mimicking the structure of the ligand-bound wild-type VEGFR-2 dimer. Quantitative FRET, biochemical phosphorylation analysis, site-directed mutagenesis eLife High 27052508
2011 Thermodynamic analysis showed that VEGF-A, VEGF-C, and VEGF-E binding to VEGFR-2 full-length extracellular domain (ECD) is 1.0–1.7 kcal/mol less favorable than binding to the isolated ligand-binding domains 2–3 (D23), consistent with energetically unfavorable homotypic interactions in domains D4–7 that enforce receptor monomer re-orientation and thereby prevent ligand-independent activation. Crystal structures of VEGF-A and VEGF-E with D23 revealed comparable binding surfaces but variation in D23 twist angles. Isothermal titration calorimetry, small-angle X-ray scattering, X-ray crystallography Blood High 22207738
2012 VEGFR-1 and VEGFR-2 form heterodimers (VEGFR1-2). Activation of VEGFR1-2 with a synthetic bispecific ligand (VEGF-E/PlGF-1) mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation, and vasorelaxation via the nitric oxide pathway, but does NOT mediate proliferation or endothelial tissue factor production (functions controlled by VEGFR-2 homodimers). VEGFR1-2 activation also inhibits VEGF-A-induced prostacyclin release, ERK1/2 phosphorylation, and intracellular calcium mobilization. Bispecific synthetic ligand stimulation, phosphorylation assays, endothelial cell functional assays (migration, tube formation, proliferation), nitric oxide pathway analysis Nature communications High 22828632
2005 Down-regulation of VEGFR-2 is mediated by PKC (non-classical isoforms) and requires at least 39 amino acids in the carboxyl-terminal domain immediately C-terminal to the kinase domain, including serine residues at positions 1188 and 1191. Mutation of these serines compromised ligand-dependent receptor down-regulation. c-Cbl promotes VEGFR-2 phosphorylation but does not mediate ubiquitylation or down-regulation of VEGFR-2. Structure-function analysis with progressive deletion mutants, pharmacological PKC inhibition, site-directed mutagenesis of serine residues, VEGFR-2 down-regulation assays Molecular biology of the cell High 15673613
2003 Chimeric receptor studies using CSF-1R extracellular domain fused to VEGFR-2 cytoplasmic domain showed selective activation of VEGFR-2 (not VEGFR-1) stimulates endothelial cell growth, migration, and differentiation. Site-directed mutagenesis identified tyrosines 799 and 1173 as required for VEGFR-2-mediated endothelial cell growth and PI3K activation, and tyrosine 1212 (in the carboxyl tail) as required for ligand-dependent autophosphorylation and signaling protein activation. Chimeric receptor construction, site-directed mutagenesis, endothelial cell growth/migration/differentiation assays, PI3K activation assays Annals of the New York Academy of Sciences Medium 12814952
2013 VEGFR-2 is methylated at multiple lysine and arginine residues including Lys1041, which is proximal to the kinase domain activation loop. Methylation at Lys1041 is independent of ligand binding and is not regulated by ligand stimulation, but enhances tyrosine phosphorylation and kinase activity in response to ligands. Pharmacological inhibition of methylation or K1041 mutagenesis abrogated VEGFR-2-mediated angiogenesis in zebrafish and tumor growth in mice. Mass spectrometry identification of methylation sites, site-directed mutagenesis, pharmacological methyltransferase inhibition, zebrafish angiogenesis assay, mouse tumor growth assay Science signaling High 24300896
2015 Phosducin-like 3 (PDCL3), a chaperone protein, directly interacts with VEGFR-2 and protects it from misfolding and aggregation, thereby regulating its expression level. N-terminal methionine acetylation of PDCL3 is required for this interaction; a PDCL3 mutant unable to undergo acetylation was refractory to hypoxia-induced upregulation. siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression and VEGF-induced VEGFR-2 phosphorylation, while PDCL3 overexpression increased VEGFR-2 protein. PDCL3 expression is induced by hypoxia. Co-immunoprecipitation, siRNA knockdown, overexpression, VEGFR-2 phosphorylation assays, zebrafish and mouse angiogenesis models, protein aggregation assay Angiogenesis Medium 26059764
2015 RNF121, an ER-localized ubiquitin E3 ligase, recognizes newly synthesized VEGFR-2 in the endoplasmic reticulum and controls its trafficking and maturation. Overexpression of RNF121 promoted VEGFR-2 ubiquitination, inhibited its maturation, and reduced VEGFR-2 cell surface presence. shRNA knockdown of RNF121 reduced VEGFR-2 ubiquitination and increased cell surface VEGFR-2. The RING Finger domain of RNF121 is required for its activity. RNF121 overexpression inhibited VEGF-induced endothelial cell proliferation and angiogenesis. Co-immunoprecipitation, ubiquitination assays, shRNA knockdown, overexpression, RING domain deletion mutants, cell surface VEGFR-2 measurement, endothelial proliferation and angiogenesis assays Traffic (Copenhagen, Denmark) Medium 26602861
2012 CD146 directly interacts with VEGFR-2 on endothelial cells and is required for VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation, endothelial cell migration, and microvascular formation. Anti-CD146 antibody (AA98) or CD146 siRNA abrogates VEGFR-2 activation by VEGF. In vivo, VEGF-promoted microvascular formation was impaired in endothelial-specific CD146 knockout mice. Co-immunoprecipitation, pulldown, structural domain identification, siRNA knockdown, anti-CD146 antibody, conditional knockout mice, in vivo angiogenesis assay, tumor xenograft Blood High 22718841
2015 EMMPRIN/CD147 directly interacts with VEGFR-2 extracellular domain and acts as a coreceptor, regulating VEGFR-2 activation by VEGF. Computational docking and mutagenesis studies identified the EMMPRIN binding site at amino acids 195/199 in the extracellular domain close to the cell membrane. EMMPRIN overexpression potentiates VEGFR-2 activation. Co-immunoprecipitation, computational docking, mutagenesis, in vitro and in vivo angiogenesis assays Oncotarget Medium 25825981
2007 VEGF stimulation of endothelial cells induces FLT-1 (VEGFR-1)-mediated internalization of KDR (VEGFR-2) to the nucleus via microtubules and the endocytic pathway, requiring PI3-kinase/AKT activation and receptor phosphorylation (tyrosine activation). KDR deletion mutants in several tyrosine residues showed impaired VEGF-induced internalization. In vitro wounding of endothelial monolayers leads to rapid internalization of VEGF+KDR to the nucleus, which is essential for monolayer recovery. FLT-1 blockade prevents VEGF and KDR activation and internalization, blocking endothelial monolayer recovery. KDR deletion mutants, PI3K inhibition, antibody blockade of FLT-1, nuclear fractionation, in vitro wound healing assay Experimental cell research Medium 17382929
2006 Neuropilin-2 (NRP2) interacts with VEGFR-2 in response to VEGF-A and VEGF-C stimulation in primary human endothelial cells. This interaction correlates with enhanced VEGFR-2 phosphorylation threshold. NRP2 overexpression promotes endothelial cell survival induced by VEGF-A and VEGF-C, while siRNA targeting NRP2 inhibits endothelial cell migration induced by these ligands. SEMA3F (a NRP2 ligand) inhibits endothelial cell survival and migration induced by VEGF-A and VEGF-C. Co-immunoprecipitation, NRP2 siRNA knockdown, NRP2 overexpression, endothelial cell survival and migration assays Blood Medium 16621967
2006 Neuropilin-1 (NP1) and neuropilin-2 (NP2) enhance VEGF121-stimulated VEGFR-2 phosphorylation and VEGF121-induced endothelial cell proliferation. NP1 enhancement of VEGF121 (which does not bind neuropilins) was accompanied by a 10-fold increase in VEGF121 binding affinity to VEGFR-2 and was not associated with formation of new VEGFR-2/NP1 complexes, suggesting that pre-formed spontaneous VEGFR-2/NP1 complexes are sufficient for neuropilin-mediated enhancement. VEGF165 does not stabilize VEGFR-2/NP1 complexes by forming bridges. VEGFR-2 phosphorylation assays, VEGF binding affinity measurements, complex formation analysis, endothelial cell proliferation assays, VEGF165KF neuropilin-binding mutant FASEB journal Medium 17185751
2010 VEGFR-2 is expressed by neurons of the subiculum in the mouse brain and mediates axonal elongation in response to semaphorin 3E (Sema3E), independent of VEGF ligands. VEGFR-2 associates with the PlexinD1/Neuropilin-1 receptor complex and becomes tyrosine-phosphorylated upon Sema3E stimulation. Sema3E triggers VEGFR-2-dependent activation of the PI3K/Akt pathway required for the increase in axonal growth. In vivo mouse genetic analysis (VEGFR-2 neuronal expression), co-immunoprecipitation showing VEGFR-2/PlexinD1/NRP1 complex, VEGFR-2 phosphorylation assay upon Sema3E stimulation, PI3K/Akt pathway analysis, axonal growth assays Neuron High 20434998
2013 G protein G13 controls VEGFR-2 expression in endothelial cells through activation of small GTPase RhoA and transcription factor NF-κB, which acts via a specific binding site at position -84 of the VEGFR-2 promoter. Endothelial cell-specific loss of G13 in mice reduces VEGFR-2 expression at sites of angiogenesis, impairs VEGF-A responsiveness, and results in defective retinal angiogenesis and tumor vascularization. VEGFR-2 level normalization rescues the phenotype. Endothelial-specific conditional G13 knockout mice, VEGFR-2 promoter NF-κB binding site analysis, RhoA activation assays, rescue experiments with VEGFR-2 normalization Developmental cell High 23664862
2012 DNA methylation of CpG islands in the KDR promoter region silences VEGFR-2 (KDR) expression. In cell lines where the KDR promoter is hypermethylated, VEGFR-2 is not expressed, and treatment with the DNA demethylating agent 5-Aza-2'deoxycytidine re-induces KDR expression. Bisulfite sequencing, methylation-specific PCR (MSP), 5-Aza-2'deoxycytidine treatment, RT-PCR, Western blot BMC cancer Medium 22251800
2017 RCAN1.4 (Regulator of calcineurin 1, isoform 4) regulates agonist-stimulated VEGFR-2 internalization and establishment of endothelial cell polarity. siRNA-mediated silencing of RCAN1 impaired VEGF-mediated cytoskeletal reorganization, directed cell migration, and sprouting angiogenesis. Adenoviral overexpression of RCAN1.4 increased endothelial cell migration. Morpholino silencing of zebrafish RCAN1.4 orthologue disrupted vascular development. siRNA knockdown, adenoviral overexpression, VEGFR-2 internalization assay, zebrafish morpholino knockdown, endothelial migration and sprouting assays Angiogenesis Medium 28271280
2017 Matrix stiffness modulates VEGFR-2 internalization and downstream signaling. Stiffer matrices induce increased VEGFR-2 internalization via actin-mediated contractility (ROCK-dependent), resulting in elevated ERK1/2 phosphorylation and increased cell proliferation. More compliant matrices correlate with increased VEGFR-2 expression and clustering. ROCK inhibition on stiff substrates increased VEGFR-2 clustering and decreased internalization. These stiffness-enhanced VEGF signaling effects are lost at cell confluency. Tunable hydrogel substrates, VEGFR-2 internalization assay, ROCK inhibition, ERK1/2 phosphorylation assay, cell proliferation assay, VEGFR-2 clustering analysis Convergent science physical oncology Medium 29531793
2017 Autophagy in glioma stem cells (GSCs) promotes VEGFR-2 (KDR) phosphorylation through ROS-mediated PI3K/AKT pathway activation, independently of VEGF. Rapamycin (autophagy inducer) increased VEGFR-2 phosphorylation and vasculogenic mimicry formation; chloroquine or ATG5 knockdown inhibited VEGFR-2 phosphorylation and vasculogenic mimicry. Neutralization of VEGF by bevacizumab failed to replicate the effect of autophagy inhibition, indicating VEGF-independent KDR activation by ROS. 3D collagen scaffold VM formation assay, rapamycin/chloroquine treatment, ATG5 siRNA knockdown, ROS measurement, N-acetylcysteine ROS inhibition, VEGFR-2 phosphorylation assays Autophagy Medium 28812437
2008 Autocrine VEGF-VEGFR2 (KDR) signaling in glioblastoma cells modulates cell cycle progression and cell viability, involving co-activation of c-Raf/MAPK, PI3K/Akt, and PLC/PKC pathways. Selective blockade of VEGFR2 with inhibitor SU1498 abrogated VEGF-mediated enhancement of astrocytoma cell growth and potentiated ionizing radiation-induced tumor cell death. VEGFR-2 selective inhibitor (SU1498) treatment, cell cycle analysis, viability assays, pathway phosphorylation assays (MAPK, Akt, PKC) Cell cycle (Georgetown, Tex.) Medium 18719373
2010 Claudin-like protein 24 (CLP24) interacts with VEGFR-2 and VEGFR-3, attenuates CREB phosphorylation via these receptors, and regulates lymphatic vessel development. Clp24 knockout in mice showed enlarged lymphatic vessels with abnormal smooth muscle cell coating, and the phenotype was aggravated in Vegfr2(+/LacZ) or Vegfr3(+/LacZ) backgrounds. Co-immunoprecipitation, Clp24 knockout mice, Vegfr2/Vegfr3 heterozygous genetic interaction (epistasis), zebrafish/Xenopus morpholino knockdown, CREB phosphorylation assays Genes & development High 20439428
2014 GABARBP (GABA-A receptor-binding protein) directly binds VEGFR-2 and inhibits VEGF-induced VEGFR-2 phosphorylation, thereby blocking activation of downstream PI3K components PDK1, Akt, mTOR, TSC-2, p70S6K, and 4E-BP1. GABARBP overexpression inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation, and decreased VEGF and HIF-1α protein expression. Co-immunoprecipitation (direct binding), VEGFR-2 phosphorylation assays, PI3K pathway phosphorylation analysis, endothelial cell functional assays Cellular signalling Medium 24686084
2016 CLEC14A forms a complex with VEGFR-3 in endothelial cells and regulates the balance between VEGFR-2 and VEGFR-3 signaling. CLEC14A knockout results in marked reduction of VEGFR-3 concomitant with increased VEGFR-2 expression and downstream signaling, leading to enhanced angiogenic sprouting and hemorrhage. Blockade of VEGFR-2 signaling suppressed vascular abnormalities in CLEC14A-KO tumor-bearing mice. CLEC14A knockout mice, VEGFR-2/VEGFR-3 expression and signaling assays, VEGFR-2 blockade rescue experiments, in vivo tumor angiogenesis assays The Journal of clinical investigation High 27991863
2013 Endothelial VEGFR-2 is cooperatively required for both migration and proliferation of lymphatic endothelial cells (LECs), together with VEGFR-3, during the early migration phase of lymphangiogenesis. However, VEGFR-3 is redundant with VEGFR-2 for LEC organization into functional capillaries. Co-neutralization of both VEGFR-2 and VEGFR-3 (but not either alone) completely prevented lymphatic organization in vivo. Selective antagonist monoclonal antibodies (DC101 for VEGFR-2, mF4-31C1 for VEGFR-3) in vivo and in vitro; LEC migration, proliferation, and tubulogenesis assays in 3D culture; adult lymphangiogenesis model in regenerating skin FASEB journal High 17210781
2000 VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A in vasculogenesis and hematopoiesis in mouse embryos. In VEGFR-3-deficient embryos, excess VEGF-C signals through VEGFR-2 and induces disturbance of vasculogenesis and hematopoiesis. VEGF-C signals through VEGFR-2 can promote vascular bed formation, and blocking VEGF-C (via VEGFR-3-Fc) in VEGFR-3-deficient embryos suppressed vascular bed formation and partially rescued hematopoiesis. Para-aortic splanchnopleural mesoderm coculture with OP9 stromal cells, soluble receptor competitor proteins (VEGFR-1-Fc, VEGFR-3-Fc), VEGFR-3-deficient mouse embryos Blood Medium 11090062
2018 Mice heterozygous for Vegfr2 (Flk1) display profound defects in tumor angiogenesis and tumor growth across multiple mouse tumor models (chemical carcinogenesis, B16F0 melanoma, Lewis Lung Carcinoma). Hematopoietic deletion of two Vegfr2 alleles had minimal impact on tumor growth or angiogenesis, demonstrating that endothelial Vegfr2 gene dosage is the critical determinant. Additional deletion of endothelial Fgfr1 and Fgfr2 in Vegfr2 heterozygous mice showed no synergistic effect on tumor growth. Vegfr2 heterozygous and conditional knockout mice, multiple independent tumor models, hematopoietic vs endothelial cell-specific deletion Scientific reports High 30283071
2000 VEGFR-2 expressed on leukemic cells is functional: VEGF165 induces phosphorylation of VEGFR-2 and increases leukemic cell proliferation via an autocrine loop. VEGF165 also induces MMP-9 expression by leukemic cells and promotes their migration through reconstituted basement membrane. The neutralizing anti-KDR mAb IMC-1C11 inhibited leukemic cell survival and VEGF-induced proliferation and migration in vitro, and blocked human leukemia xenograft growth in vivo. VEGFR-2 phosphorylation assay, proliferation assays, MMP-9 expression assay, migration through Matrigel, neutralizing antibody inhibition, human leukemia xenograft in NOD/SCID mice The Journal of clinical investigation High 10953026
1998 Anti-KDR monoclonal antibodies (generated by hybridoma and phage display) compete equimolarly with VEGF for binding to KDR and inhibit VEGF-induced signaling and mitogenesis in human endothelial cells with similar potency to the anti-mouse VEGFR2 antibody DC101, which blocks VEGF binding to the receptor and inhibits tumor growth through anti-angiogenic mechanism. Competitive binding assays (mAb vs VEGF on KDR), VEGF-induced signaling inhibition assays, endothelial cell mitogenesis assays, in vivo mouse tumor model with DC101 Cancer metastasis reviews Medium 9770111
2014 A germline variant rs34231037 (C482R) in KDR explains 23% of the variance in serum soluble VEGFR-2 (sVEGFR-2) concentrations. In a structural context, this C482R mutation in VEGFR-2 promotes ligand-independent signaling by mimicking the ligand-bound active conformation (consistent with FRET structural data from the same variant in a separate study). rs34231037 also predicts changes in sVEGFR-2 in response to pazopanib treatment. Genome-wide association study (GWAS) of sVEGFR-2 in healthy Amish volunteers, replication in cancer patients, pharmacodynamic analysis during pazopanib therapy Clinical cancer research Low 25411163

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 1789 10648408
2000 Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. The Journal of clinical investigation 388 10953026
1998 Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer metastasis reviews 280 9770111
2006 Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 235 16621967
1999 Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Investigative ophthalmology & visual science 197 10440268
2006 VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Frontiers in bioscience : a journal and virtual library 174 16146773
2012 CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood 163 22718841
2011 Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization. Blood 129 22207738
2012 The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. Nature communications 126 22828632
2021 Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions. Current drug metabolism 123 33076807
2017 Autophagy-induced KDR/VEGFR-2 activation promotes the formation of vasculogenic mimicry by glioma stem cells. Autophagy 123 28812437
2008 Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay. Cell cycle (Georgetown, Tex.) 119 18719373
2007 Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 119 17210781
2000 VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood 117 11090062
2010 VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain. Neuron 112 20434998
2007 VEGF and VEGFR-2 (KDR) internalization is required for endothelial recovery during wound healing. Experimental cell research 112 17382929
2004 Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung cancer (Amsterdam, Netherlands) 110 15364128
2016 VEGFR-2 conformational switch in response to ligand binding. eLife 107 27052508
2003 Tumor specific VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer. Breast cancer research and treatment 104 14703061
2023 Recent development of multi-target VEGFR-2 inhibitors for the cancer therapy. Bioorganic chemistry 95 36801788
2017 VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016). Expert opinion on therapeutic patents 95 28621580
2005 The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Human pathology 88 16426919
2007 Activated VEGFR2/KDR pathway in tumour cells and tumour associated vessels of colorectal cancer. European journal of clinical investigation 77 17883421
2021 New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis. Bioorganic chemistry 75 33721808
2012 Development and strategies of VEGFR-2/KDR inhibitors. Future medicinal chemistry 73 23043480
2017 Matrix Stiffness Enhances VEGFR-2 Internalization, Signaling, and Proliferation in Endothelial Cells. Convergent science physical oncology 67 29531793
2011 VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. International journal of cancer 67 20473929
2001 Expression and function of CD105 during the onset of hematopoiesis from Flk1(+) precursors. Blood 67 11739167
2005 The carboxyl terminus of VEGFR-2 is required for PKC-mediated down-regulation. Molecular biology of the cell 65 15673613
2002 Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships. Current topics in medicinal chemistry 64 12171566
2015 The Emerging Regulation of VEGFR-2 in Triple-Negative Breast Cancer. Frontiers in endocrinology 61 26500608
2019 Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors. European journal of medicinal chemistry 60 30826508
2017 RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. Angiogenesis 57 28271280
2006 Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 54 17185751
2013 G13 controls angiogenesis through regulation of VEGFR-2 expression. Developmental cell 52 23664862
2021 An updated patent review of VEGFR-2 inhibitors (2017-present). Expert opinion on therapeutic patents 51 34043477
2015 Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment. Liver international : official journal of the International Association for the Study of the Liver 51 25559745
2010 RETRACTED: Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer research 51 20978198
2003 Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice. Atherosclerosis 51 14642407
2016 Expressions of VEGF-A and VEGFR-2 in placentae from GDM pregnancies. Reproductive biology and endocrinology : RB&E 49 27645229
2010 Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades. Molecular cancer therapeutics 49 20103598
1998 Increased expression of KDR/Flk-1 (VEGFR-2) in murine model of ischemia-induced retinal neovascularization. Microvascular research 48 9828156
2009 Polymorphisms in the VEGFA and VEGFR-2 genes and neovascular age-related macular degeneration. Molecular vision 47 20019880
1999 VEGF, VEGFR-1, VEGFR-2, microvessel density and endothelial cell proliferation in tumours of the ovary. International journal of cancer 47 10096239
2015 Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget 46 25682871
2006 Expression of VEGFR-2 on HaCaT cells is regulated by VEGF and plays an active role in mediating VEGF induced effects. Biochemical and biophysical research communications 46 16930552
2002 Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1 expression. Kidney international 44 11967019
2001 Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast. Histology and histopathology 44 11332691
2023 New benzothiazole hybrids as potential VEGFR-2 inhibitors: design, synthesis, anticancer evaluation, and in silico study. Journal of enzyme inhibition and medicinal chemistry 43 36691927
2015 Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis 43 26059764
2022 Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation. Molecules (Basel, Switzerland) 41 35956997
2005 VEGF and VEGFR-2 immunohistochemistry in human melanocytic naevi and cutaneous melanomas. Melanoma research 40 15714119
2015 EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF. Oncotarget 38 25825981
2011 Clinical significance of VEGFR-2 and VEGFR-3 expression in ovarian cancer patients. Polish journal of pathology : official journal of the Polish Society of Pathologists 38 21574104
2003 Comparative structure-function analysis of VEGFR-1 and VEGFR-2: What have we learned from chimeric systems? Annals of the New York Academy of Sciences 36 12814952
2015 Expression and localization of vascular endothelial growth factor A (VEGFA) and its two receptors (VEGFR1/FLT1 and VEGFR2/FLK1/KDR) in the canine corpus luteum and utero-placental compartments during pregnancy and at normal and induced parturition. General and comparative endocrinology 35 26414127
2015 PET Imaging of VEGFR-2 Expression in Lung Cancer with 64Cu-Labeled Ramucirumab. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 35 26541778
2017 New Coumarin Derivatives as Anti-Breast and Anti-Cervical Cancer Agents Targeting VEGFR-2 and p38α MAPK. Archiv der Pharmazie 34 28787092
2022 New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation. Drug design, development and therapy 33 35281317
2023 Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors. Journal of enzyme inhibition and medicinal chemistry 32 37122176
2012 DNA methylation regulates expression of VEGF-R2 (KDR) and VEGF-R3 (FLT4). BMC cancer 32 22251800
2016 Carbohydrate-binding protein CLEC14A regulates VEGFR-2- and VEGFR-3-dependent signals during angiogenesis and lymphangiogenesis. The Journal of clinical investigation 30 27991863
2024 Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents. RSC advances 29 39439843
2016 Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nature communications 29 27453397
2010 Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development. Genes & development 29 20439428
2020 Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib. International journal of molecular sciences 28 33255816
2017 Distinct transcriptional responses of lymphatic endothelial cells to VEGFR-3 and VEGFR-2 stimulation. Scientific data 28 28850122
2013 Lysine methylation promotes VEGFR-2 activation and angiogenesis. Science signaling 27 24300896
2004 Expression of VEGFR-1 and VEGFR-2 in degenerative Achilles tendons. Clinical orthopaedics and related research 27 15057110
2016 Selective Imaging of VEGFR-1 and VEGFR-2 Using 89Zr-Labeled Single-Chain VEGF Mutants. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 26 27390161
2023 Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase. Molecules (Basel, Switzerland) 25 36677750
2013 Blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in gastric cancer cells. Yonsei medical journal 25 23364970
2013 Attenuation of VEGFR-2 expression by sFlt-1 and low oxygen in human placenta. PloS one 25 24260556
2012 Differential expression of Vegfr-2 and its soluble form in preeclampsia. PloS one 25 22428059
2007 The role of VEGF and VEGFR2/Flk1 in proliferation of retinal progenitor cells in murine retinal degeneration. Investigative ophthalmology & visual science 25 17724222
2018 Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1). Scientific reports 24 30283071
2017 MicroRNA-497 suppresses renal cell carcinoma by targeting VEGFR-2 in ACHN cells. Bioscience reports 24 28465356
2020 Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer. Molecules (Basel, Switzerland) 22 33050377
2022 Elucidating Antiangiogenic Potential of Rauwolfia serpentina: VEGFR-2 Targeting-Based Molecular Docking Study. Evidence-based complementary and alternative medicine : eCAM 21 35198035
2021 Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma. Cancers 21 33401382
2021 Sorafenib derivatives-functionalized gold nanoparticles confer protection against tumor angiogenesis and proliferation via suppression of EGFR and VEGFR-2. Experimental cell research 21 34089726
2016 Elevated Expression of VEGF-C and Its Receptors, VEGFR-2 and VEGFR-3, in Patients with Mesial Temporal Lobe Epilepsy. Journal of molecular neuroscience : MN 21 26798047
2014 GABARBP down-regulates HIF-1α expression through the VEGFR-2 and PI3K/mTOR/4E-BP1 pathways. Cellular signalling 21 24686084
2008 Localization and control of expression of VEGF-A and the VEGFR-2 receptor in fetal sheep intestines. Pediatric research 21 18091346
2014 Identification of a variant in KDR associated with serum VEGFR2 and pharmacodynamics of Pazopanib. Clinical cancer research : an official journal of the American Association for Cancer Research 20 25411163
2012 CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. Journal of molecular medicine (Berlin, Germany) 20 22935775
2022 Design and synthesis of new 2-oxoquinoxalinyl-1,2,4-triazoles as antitumor VEGFR-2 inhibitors. Bioorganic chemistry 19 35217379
2021 Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazoline and diarylamide fragments. Bioorganic & medicinal chemistry letters 19 33460739
2021 Silencing VEGFR-2 Hampers Odontoblastic Differentiation of Dental Pulp Stem Cells. Frontiers in cell and developmental biology 19 34249919
2019 Single cell transcriptome dynamics from pluripotency to FLK1+ mesoderm. Development (Cambridge, England) 19 31740535
2007 FGFs, Wnts and BMPs mediate induction of VEGFR-2 (Quek-1) expression during avian somite development. Developmental biology 19 17425953
2007 Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 19 17703341
2023 Rationale design and synthesis of new apoptotic thiadiazole derivatives targeting VEGFR-2: computational and in vitro studies. RSC advances 18 38116168
2019 KDR (VEGFR2) Genetic Variants and Serum Levels in Patients with Rheumatoid Arthritis. Biomolecules 18 31405022
2015 TTAC-0001, a human monoclonal antibody targeting VEGFR-2/KDR, blocks tumor angiogenesis. mAbs 18 25942475
2023 New proapoptotic chemotherapeutic agents based on the quinolone-3-carboxamide scaffold acting by VEGFR-2 inhibition. Scientific reports 17 37443185
2015 CD144, CD146 and VEGFR-2 properly identify circulating endothelial cell. Revista brasileira de hematologia e hemoterapia 16 25818819
2015 RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR-2. Traffic (Copenhagen, Denmark) 16 26602861
2014 2-Methoxyestradiol regulates VEGFR-2 and sFlt-1 expression in human placenta. Placenta 16 25499009
2023 Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations. Journal of biomolecular structure & dynamics 15 37261471

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