Affinage

KDR

Vascular endothelial growth factor receptor 2 · UniProt P35968

Round 2 corrected
Length
1356 aa
Mass
151.5 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDR (VEGFR-2) is the principal receptor tyrosine kinase transducing VEGF-A signals that drive endothelial cell survival, proliferation, migration, and angiogenic sprouting (PMID:7929439, PMID:12810700). Upon VEGF-A binding (KD ~75 pM), KDR autophosphorylates at key tyrosines—Y1175 activates PLCγ/MAPK-dependent mitogenesis and Y1214 contributes additional signaling—while the PI3K/Akt axis mediates endothelial survival, and c-Src recruitment drives nitric oxide and prostacyclin production (PMID:11387210, PMID:9804796, PMID:10455194). Receptor activity is tuned by co-receptors (NRP1/2, αvβ3 integrin, VE-cadherin, CD146) that modulate ligand binding affinity, autophosphorylation, and clathrin-dependent internalization; VE-cadherin retains KDR at junctions where the phosphatase DEP-1 limits signaling, whereas internalized KDR sustains endosomal ERK activation (PMID:17185751, PMID:10022831, PMID:10428027, PMID:22718841, PMID:16893970). Post-translational regulation includes lysine methylation at K1041 that primes kinase activity, PKC-dependent serine phosphorylation (S1188/S1191) governing receptor downregulation, ER-resident RNF121-mediated ubiquitination controlling surface trafficking, and cross-talk with PDGF-Rβ and MET heterocomplexes that coordinate vessel maturation and tumor cell invasion (PMID:24300896, PMID:15673613, PMID:26602861, PMID:18997771, PMID:22789536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1991 High

    Identification of KDR as a novel type III receptor tyrosine kinase in endothelial cells established the molecular identity of a candidate vascular signaling receptor.

    Evidence cDNA cloning from human endothelial cell library with sequence and chromosomal localization

    PMID:1656371

    Open questions at the time
    • No ligand identified at this point
    • Kinase activity not demonstrated biochemically
    • Expression pattern beyond endothelium unknown
  2. 1992 High

    Demonstrating that KDR binds VEGF with high affinity (KD ~75 pM) answered the key question of ligand identity and positioned KDR as a functional VEGF receptor.

    Evidence 125I-VEGF binding and affinity cross-linking in heterologous cells expressing KDR

    PMID:1417831

    Open questions at the time
    • Signaling consequences of binding not yet tested
    • Relationship to the other VEGF receptor Flt1 unclear
  3. 1994 High

    Functional reconstitution revealed that KDR, not Flt1, mediates VEGF-induced mitogenesis, chemotaxis, and actin reorganization, resolving which receptor drives the major endothelial biological responses.

    Evidence Stable expression of human KDR vs Flt1 in porcine aortic endothelial cells with multiple phenotypic readouts

    PMID:7929439

    Open questions at the time
    • Downstream signaling pathways not delineated
    • In vivo relevance not yet shown
  4. 1996 High

    Alanine-scanning mutagenesis of VEGF defined the receptor-binding determinants, showing distinct residues govern KDR vs Flt1 recognition and that KDR binding is necessary for mitogenesis.

    Evidence Site-directed VEGF mutagenesis with receptor binding and endothelial proliferation assays

    PMID:8621427

    Open questions at the time
    • Structural basis of the VEGF–KDR interface not yet resolved
    • Whether additional VEGF family members bind KDR unknown
  5. 1998 High

    Identification of the PI3K/Akt survival pathway downstream of KDR, and demonstration that VEGF-D and VEGF-C also serve as KDR ligands, expanded the receptor's signaling repertoire and ligand family.

    Evidence Receptor-selective VEGF mutants, dominant-negative Akt, PI3K inhibitors for survival; direct binding/activation assays for VEGF-D

    PMID:9435229 PMID:9804796

    Open questions at the time
    • Specific autophosphorylation sites mediating each pathway unknown
    • In vivo role of VEGF-D/KDR axis undefined
  6. 1999 High

    Three co-regulatory mechanisms were uncovered simultaneously: c-Src recruitment drives NO/prostacyclin production, αvβ3 integrin enhances KDR signaling on specific ECM substrates, and VE-cadherin complexes with KDR to enable Akt/Bcl-2 survival signaling.

    Evidence Co-immunoprecipitation of KDR–c-Src, KDR–αvβ3, and KDR–VE-cadherin complexes with functional epistasis in endothelial cells and VE-cadherin knockout mice

    PMID:10022831 PMID:10428027 PMID:10455194

    Open questions at the time
    • Stoichiometry and structural basis of these multiprotein complexes unknown
    • Relative contribution of each co-receptor in vivo not separated
  7. 2001 High

    Phosphosite mapping identified Y1175 as the major autophosphorylation site required for PLCγ/MAPK activation and DNA synthesis, providing the first residue-level wiring diagram of KDR signaling.

    Evidence In vitro kinase assay, tryptic peptide mapping, Y→F mutagenesis with functional validation in endothelial cells

    PMID:11387210 PMID:12814952

    Open questions at the time
    • Full phosphosite catalog incomplete
    • Which adaptor proteins dock at Y1175 vs Y1214 not resolved
  8. 2002 High

    NRP1 was shown to form a VEGF165-dependent ternary complex with KDR, enhancing ligand binding and providing a mechanistic basis for isoform-specific signaling.

    Evidence Co-immunoprecipitation, 125I-VEGF165 radioligand binding, juxtacrine co-culture assay

    PMID:11948691

    Open questions at the time
    • Whether NRP1 modulates specific downstream pathways not yet defined
    • Structural basis of the ternary complex unknown
  9. 2003 High

    In vivo studies revealed KDR as the receptor guiding angiogenic tip cell filopodia and stalk cell proliferation, and uncovered VEGFR-1/VEGFR-2 cross-talk through heterodimer transphosphorylation and regulation by TIMPs.

    Evidence Retinal angiogenesis imaging with VEGFR-2 blockade; receptor heterodimerization assays; TIMP-2/TIMP-3 binding competition and PTP modulation of KDR

    PMID:12652295 PMID:12796773 PMID:12810700 PMID:12887919

    Open questions at the time
    • Tip-stalk cell fate decision mechanism downstream of KDR not fully defined
    • Quantitative contribution of TIMP regulation in vivo unclear
  10. 2005 High

    Two trafficking control mechanisms were defined: PKC-dependent downregulation requiring S1188/S1191 in the C-terminal tail, and dynamin-2-dependent endocytosis essential for KDR signaling and cell survival.

    Evidence C-terminal deletion/mutagenesis with PKC inhibitors; dominant-negative dynamin-2 with co-IP and survival assays

    PMID:15673613 PMID:16049137

    Open questions at the time
    • Identity of ubiquitin ligase for surface KDR turnover unknown at this stage
    • Endosomal vs plasma membrane signaling contributions not quantified
  11. 2006 High

    VE-cadherin was shown to restrain KDR internalization at junctions via DEP-1 phosphatase activity, while NRP1/2 enhancement of KDR signaling was found to occur through pre-formed complexes independent of ligand bridging, refining the spatial model of receptor regulation.

    Evidence VE-cadherin and DEP-1 siRNA with endosomal co-localization imaging; NRP overexpression with VEGF121/165 binding and phosphorylation assays

    PMID:16893970 PMID:17185751

    Open questions at the time
    • How junction disassembly is coordinated with KDR internalization kinetics in vivo not resolved
    • Structural basis of constitutive NRP-KDR interaction unknown
  12. 2008 High

    Discovery that KDR forms a heterocomplex with PDGF-Rβ to suppress pericyte signaling revealed a non-canonical role for KDR in coordinating vessel maturation beyond endothelial-autonomous signaling.

    Evidence Co-immunoprecipitation of PDGF-Rβ/VEGFR-2, VEGF genetic deletion, in vivo tumor vessel maturation assays

    PMID:18997771

    Open questions at the time
    • Whether this complex forms in normal developmental angiogenesis unclear
    • Signaling intermediates within the heterocomplex not defined
  13. 2011 High

    Biophysical and structural studies showed homotypic D4-7 interactions in the KDR ectodomain impose an energetic penalty that prevents ligand-independent activation, explaining the autoinhibitory architecture.

    Evidence ITC, SAXS, and X-ray crystallography of VEGFR-2 ECD and domain fragments

    PMID:22207738

    Open questions at the time
    • Full-length receptor structure including transmembrane and kinase domains not solved
    • How ligand binding overcomes the D4-7 autoinhibition structurally not resolved
  14. 2012 High

    CD146 was identified as a new KDR co-receptor required for VEGF-induced phosphorylation, and KDR was found to form a MET heterocomplex that recruits PTP1B to suppress tumor invasion, revealing kinase-independent scaffolding functions.

    Evidence Endothelial CD146 conditional knockout with co-IP and angiogenesis assays; MET/VEGFR-2 co-IP with PTP1B recruitment in glioblastoma models

    PMID:22718841 PMID:22789536

    Open questions at the time
    • Domain mapping of CD146–KDR interaction not done
    • Whether MET–KDR complex exists in non-tumor endothelium unknown
  15. 2013 High

    Lysine methylation at K1041 was discovered as a ligand-independent modification that primes KDR kinase activity, and G13/RhoA/NF-κB was shown to control KDR transcription, adding epigenetic and transcriptional layers to receptor regulation.

    Evidence Mass spectrometry, K1041 mutagenesis, zebrafish and mouse tumor models; endothelial G13 conditional KO with promoter dissection

    PMID:23664862 PMID:24300896

    Open questions at the time
    • Methyltransferase responsible for K1041 modification not identified
    • How G13 is activated upstream in endothelial cells not defined
  16. 2014 High

    Galectin-1 was shown to activate KDR signaling via N-glycan recognition independently of VEGF, providing a mechanistic explanation for anti-VEGF therapy resistance.

    Evidence Glycan remodeling, Gal1 binding assays, VEGFR-2 signaling in endothelial cells, in vivo tumor models with glycosyltransferase manipulation

    PMID:24529377

    Open questions at the time
    • Whether other galectins activate KDR similarly not tested
    • Clinical relevance to anti-VEGF resistance in human patients not validated
  17. 2015 High

    ER-resident E3 ligase RNF121 was identified as a quality-control checkpoint that ubiquitinates newly synthesized KDR to limit its surface delivery, establishing biosynthetic regulation as a receptor activity control point.

    Evidence RNF121 knockdown/overexpression, ubiquitination assay, cell-surface KDR quantification in endothelial cells

    PMID:26602861

    Open questions at the time
    • Ubiquitination sites on KDR targeted by RNF121 not mapped
    • Whether RNF121 regulation is dynamically controlled by angiogenic stimuli unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structural model of the KDR receptor spanning ectodomain, transmembrane, and kinase domains, the identity of the K1041 methyltransferase, and the mechanistic basis by which distinct co-receptor complexes route KDR to specific downstream pathways remain major open questions.
  • No full-length KDR structure available
  • Methyltransferase for K1041 unidentified
  • Quantitative partitioning of signaling between plasma membrane and endosomal pools in vivo not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 2 R-HSA-9612973 Autophagy 1
Partners
CDH5DNM2FLT1ITGB3MCAMMETNRP1PDGFRB
Complex memberships
VEGFR-1/VEGFR-2 heterodimerVEGFR-2/NRP1 ternary complexVEGFR-2/PDGF-Rβ heterocomplexVEGFR-2/VE-cadherin/β-catenin/PI3K complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 KDR was identified as a novel receptor tyrosine kinase cloned from a human endothelial cell cDNA library, with structural features of a type III RTK including an ATP-binding site, membrane-spanning region, and split tyrosine kinase domains; the gene is expressed as a 7.0 kb transcript and localized to human chromosome 4. cDNA library cloning, PCR with degenerate primers, sequence analysis Oncogene High 1656371
1992 KDR was identified as a high-affinity receptor for VEGF; expression of KDR in CMT-3 cells (which lack VEGF receptors) conferred saturable 125I-VEGF binding (KD = 75 pM), and affinity cross-linking labeled proteins of Mr = 195 and 235 kDa. Receptor expression in heterologous cells, 125I-VEGF binding assay, affinity cross-linking Biochemical and biophysical research communications High 1417831
1994 KDR, but not Flt1, mediates VEGF-induced actin reorganization, membrane ruffling, chemotaxis, and mitogenesis in porcine aortic endothelial cells; KDR undergoes efficient ligand-induced autophosphorylation whereas Flt1 kinase is poorly activated. Flt1 showed higher VEGF affinity (Kd 16 pM) than KDR (Kd 760 pM). Members of the Src family (Fyn, Yes) were phosphorylated by Flt1 but not KDR stimulation. Stable expression of human Flt1 and KDR in porcine aortic endothelial cells, 125I-VEGF binding, in vitro kinase assay, cell morphology and chemotaxis assays The Journal of biological chemistry High 7929439
1996 Alanine-scanning mutagenesis identified Arg82, Lys84, and His86 in a VEGF hairpin loop as critical determinants for KDR/Flk-1 binding, while Asp63, Glu64, and Glu67 are required for Flt1 binding. KDR binding (not Flt1 binding) is required for VEGF-induced endothelial cell mitogenesis. Site-directed mutagenesis of VEGF, receptor binding assays, endothelial cell proliferation assay The Journal of biological chemistry High 8621427
1998 VEGF-induced endothelial cell survival is mediated specifically through Flk-1/KDR activation of the PI3-kinase/Akt pathway; Flt1-selective ligands do not promote survival or activate Akt. A constitutively active Akt was sufficient for survival, and dominant-negative Akt blocked VEGF-induced survival. Receptor-selective VEGF mutants, PI3-kinase inhibitors (wortmannin, LY294002), dominant-negative and constitutively active Akt transfection, serum-starvation survival assay The Journal of biological chemistry High 9804796
1999 VEGF signals endothelial production of nitric oxide and prostacyclin through Flk-1/KDR activation of c-Src; immunoprecipitation showed complex formation between Flk-1/KDR and c-Src upon VEGF stimulation, and Src activation is required for downstream PLC-γ1 activation, IP3 formation, calcium release, and NOS activation. Co-immunoprecipitation, immunoassay for NO and PGI2 production, signaling cascade characterization The Journal of biological chemistry High 10455194
1999 αvβ3 integrin physically associates with tyrosine-phosphorylated VEGFR-2 (co-immunoprecipitation with β3 but not β1 or β5 subunit) following VEGF-A165 stimulation in endothelial cells; this interaction enhances VEGFR-2 phosphorylation, PI3K activation, and mitogenicity on vitronectin versus fibronectin substrates. Co-immunoprecipitation, blocking antibodies, cell adhesion on different ECM substrates, proliferation assay The EMBO journal High 10022831
1999 VE-cadherin forms a complex with VEGFR-2, β-catenin, and PI3-kinase in endothelial cells; loss of VE-cadherin or its cytoplasmic domain abolishes VEGF-A-induced Akt and Bcl-2 survival signaling, causing endothelial apoptosis and embryonic lethality. Gene targeting (VEC-/- and VECΔc/Δc mice), co-immunoprecipitation, Akt/Bcl-2 phosphorylation assays Cell High 10428027
2001 Y1175 is a major VEGF-A-dependent autophosphorylation site on KDR essential for PLC-γ phosphorylation, MAP kinase activation, and DNA synthesis in endothelial cells. The Y1175F mutant loses these responses. Y1212 in the carboxyl tail is required for ligand-dependent autophosphorylation. Y1214 is a second autophosphorylation site. In vitro kinase assay, tryptic peptide mapping, site-directed mutagenesis, adenoviral delivery of KDR mutants into endothelial cells, phospho-specific antibody microinjection The EMBO journal High 11387210
2001 Selective activation of chimeric VEGFR-2 (using a CSF-1R extracellular domain fusion) stimulates endothelial cell growth, migration, and differentiation, while chimeric VEGFR-1 does not; co-expression of chimeric VEGFR-1 suppresses VEGFR-2-mediated growth. Mutagenesis showed tyrosines 799 and 1173 are required for VEGFR-2-mediated endothelial cell growth and PI3K activation; Y1212 in the carboxyl tail is required for ligand-dependent autophosphorylation. Chimeric receptor construction, site-directed mutagenesis, endothelial cell growth/migration/differentiation assays Annals of the New York Academy of Sciences Medium 12814952
2002 VEGF165 mediates formation of a ternary complex containing VEGFR-2 (KDR) and neuropilin-1 (NRP1) on endothelial cells, increasing 125I-VEGF165 binding to KDR. This complex requires VEGF165 (VEGF121 does not support it) and can form in a juxtacrine manner between cells expressing only KDR and cells expressing only NRP1. Co-immunoprecipitation, soluble NRP1 binding assay, 125I-VEGF165 radioligand binding, co-culture assay Journal of cellular biochemistry High 11948691
2003 VEGF-A controls angiogenic sprouting by guiding filopodial extension from endothelial tip cells via VEGFR-2 agonism; tip cells respond by directed migration (dependent on a VEGF-A gradient) while stalk cells proliferate in response to VEGF-A concentration, both responses mediated by VEGFR-2. In vivo retinal angiogenesis imaging, VEGFR-2 blockade experiments, confocal microscopy of vascular sprouts The Journal of cell biology High 12810700
2003 PlGF activates Flt1 (VEGFR-1), causing intermolecular transphosphorylation of Flk1 (VEGFR-2), thereby amplifying VEGF-driven angiogenesis through Flk1. VEGF/PlGF heterodimers activate intramolecular VEGFR cross talk through formation of Flt1/Flk1 heterodimers. Receptor phosphorylation assays, gene expression profiling, in vivo ischemia angiogenesis model Nature medicine High 12796773
2003 TIMP-2 increases protein tyrosine phosphatase (PTP) activity associated with KDR, providing an MMP-independent mechanism for inhibition of endothelial cell proliferation and angiogenesis. TIMP-2 binds endothelial cells via α3β1 integrin and dissociates SHP-1 from β1 integrin. PTP activity assay, co-immunoprecipitation, α3β1 integrin binding assay, in vitro proliferation and in vivo angiogenesis assays Cell High 12887919
2003 TIMP3 blocks VEGF binding to VEGFR-2 and inhibits downstream signaling and angiogenesis, independent of MMP inhibitory activity. VEGF-VEGFR-2 binding competition assay, downstream signaling assays, angiogenesis assays Nature medicine High 12652295
2005 PKC-mediated down-regulation of VEGFR-2 requires at least 39 amino acids immediately C-terminal to the kinase domain, specifically serine residues at positions 1188 and 1191; c-Cbl promotes VEGFR-2 phosphorylation but does not mediate ubiquitination or down-regulation of VEGFR-2. The ectodomain is dispensable for PKC-dependent down-regulation. Progressive C-terminal deletion mutagenesis, pharmacological PKC inhibitors/activators, c-Cbl overexpression/knockdown, receptor down-regulation assays Molecular biology of the cell High 15673613
2005 Dynamin-2 colocalizes with KDR on the plasma membrane, endosomes, and perinuclear region of endothelial cells, co-immunoprecipitates with KDR, and is required for KDR-mediated endothelial cell signaling and survival. Overexpression of GTPase-deficient dynamin-2 (K44A) selectively reduces KDR protein level and inhibits endosomal vesicle formation. Co-immunoprecipitation, confocal colocalization, dominant-negative dynamin-2 overexpression, cell cycle/survival assays FASEB journal High 16049137
2006 VE-cadherin limits VEGFR-2 signaling by retaining it at the cell membrane and preventing clathrin-dependent internalization. When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly into endosomal compartments where it remains phosphorylated, co-distributes with active PLCγ, and activates ERK and cell proliferation. The junction-associated phosphatase DEP-1/CD148 dephosphorylates VEGFR-2 at the membrane; its silencing restores internalization. Clathrin inhibition, VEC siRNA, DEP-1 siRNA, endosomal co-localization by immunofluorescence, ERK phosphorylation/proliferation assays The Journal of cell biology High 16893970
2006 Neuropilins-1 and -2 enhance VEGFR-2 signaling by increasing VEGFR-2 binding affinity (~10-fold for NRP1) and promoting VEGFR-2 phosphorylation even for VEGF121, which does not bind neuropilins. Spontaneously formed VEGFR-2/NRP1 complexes are sufficient for neuropilin-mediated enhancement without ligand-induced bridging. VEGF165 mutant analysis, 125I-VEGF121 binding assay, VEGFR-2 phosphorylation assay, NRP1/NRP2 overexpression FASEB journal High 17185751
2007 VEGF stimulation of endothelial cells induces FLT-1-mediated internalization of KDR to the nucleus via microtubules and the endocytic pathway, requiring PI3-kinase/AKT activation and KDR tyrosine phosphorylation. In vitro wounding induces transient nuclear internalization of VEGF+KDR, which is essential for monolayer recovery. KDR deletion mutants, FLT-1 blocking antibody, PI3K inhibitors, microtubule disruption, wound healing assay with nuclear KDR imaging Experimental cell research Medium 17382929
2008 VEGF-R2 suppresses PDGF-Rβ signaling in vascular smooth muscle cells through assembly of a PDGF-Rβ/VEGF-R2 receptor complex; VEGF thereby acts as a negative regulator of pericyte function and vessel maturation. Inhibition of VEGF-R2 prevents this complex assembly and restores angiogenesis. Co-immunoprecipitation of PDGF-Rβ/VEGFR-2 complex, genetic deletion of tumor-cell VEGF, VEGFR-2 inhibition, in vivo tumor vessel maturation assays Nature High 18997771
2011 Isothermal titration calorimetry showed VEGF-A, VEGF-C, and VEGF-E binding to the full-length VEGFR-2 ECD is 1.0-1.7 kcal/mol less favorable (energetically) than to isolated domains 2-3 (D23). Small-angle X-ray scattering and crystal structures of VEGF-A or VEGF-E with D23 revealed homotypic interactions in D4-7 that are energetically unfavorable and may prevent ligand-independent receptor activation. Isothermal titration calorimetry, small-angle X-ray scattering, X-ray crystallography Blood High 22207738
2012 CD146 directly interacts with VEGFR-2 on endothelial cells and is required for VEGF-induced VEGFR-2 phosphorylation and downstream AKT/p38 MAPK/NF-κB activation; endothelial conditional knockout of CD146 impairs VEGF-promoted microvascular formation in vivo. Co-immunoprecipitation, CD146 siRNA, CD146 conditional knockout mice, endothelial cell migration/tube formation assays, in vivo angiogenesis assay Blood High 22718841
2012 VEGF directly suppresses tumor cell invasion by recruiting PTP1B to a MET/VEGFR-2 heterocomplex, thereby dephosphorylating MET and blocking HGF-dependent cell migration. VEGF blockade releases this inhibition, restoring MET activity and triggering epithelial-to-mesenchymal transition in glioblastoma. Co-immunoprecipitation of MET/VEGFR2 complex, PTP1B recruitment assay, in vivo GBM mouse models, pharmacological MET inhibition Cancer cell High 22789536
2013 Lysine methylation of VEGFR-2 at multiple residues, including Lys1041 proximal to the activation loop, enhances tyrosine phosphorylation and kinase activity in response to VEGF. Methylation is ligand-independent. Site-directed mutation of Lys1041 or pharmacological inhibition of methylation impairs VEGFR-2-mediated angiogenesis in zebrafish and tumor growth in mice. Mass spectrometry identification of methylated residues, site-directed mutagenesis, pharmacological methylation inhibition, zebrafish angiogenesis assay, mouse tumor model Science signaling High 24300896
2013 G protein G13 in endothelial cells controls VEGFR-2 expression through activation of RhoA and NF-κB acting on a specific binding site at position -84 of the VEGFR-2 promoter. Endothelial-specific G13 knockout reduces VEGFR-2 expression and impairs retinal angiogenesis and tumor vascularization. Endothelial-specific G13 conditional knockout mice, RhoA activity assay, NF-κB reporter assay with promoter mutagenesis, rescue experiments Developmental cell High 23664862
2014 Galectin-1 (Gal1) recognizes complex N-glycans on VEGFR-2 and activates VEGF-like signaling in endothelial cells independently of VEGF ligand; this glycosylation-dependent pathway preserves angiogenesis in anti-VEGF refractory tumors. α2-6-linked sialylation blocks Gal1 binding and confers VEGF sensitivity. Glycan remodeling in endothelial cells, Gal1 binding assay, VEGFR-2 downstream signaling assays, in vivo tumor models, glycosyltransferase manipulation Cell High 24529377
2015 EMMPRIN/CD147 directly interacts with VEGFR-2 as a co-receptor through a molecular binding site in the extracellular domain of EMMPRIN at amino acids 195/199; this interaction potentiates VEGF-induced VEGFR-2 activation in endothelial and tumor cells. Co-immunoprecipitation, computational docking, mutagenesis of EMMPRIN residues 195/199, VEGFR-2 phosphorylation assays, in vitro and in vivo angiogenesis assays Oncotarget Medium 25825981
2015 RNF121, an ER-localized ubiquitin E3 ligase expressed in endothelial cells, recognizes newly synthesized VEGFR-2 in the ER, promotes its ubiquitination, and inhibits its maturation and cell-surface trafficking. RNF121 knockdown reduces VEGFR-2 ubiquitination and increases its cell-surface level; the RING finger domain is required for these effects. shRNA knockdown, RNF121 overexpression, ubiquitination assay, cell-surface VEGFR-2 quantification, endothelial proliferation and angiogenesis assays Traffic High 26602861
2016 VEGFR-2 signaling is regulated at multiple levels including interacting proteins (neuropilins, integrins, protein tyrosine phosphatases), endocytosis and intracellular trafficking dynamics, and crosstalk with other endothelial signaling cascades; VEGFR-2 is the primary mediator of VEGF angiogenic signaling. Review synthesizing multiple experimental studies Nature reviews. Molecular cell biology Medium 27461391
2017 Autophagy promotes VEGFR-2 (KDR) phosphorylation and vasculogenic mimicry formation in glioma stem cells through ROS-mediated PI3K-AKT pathway activation; this is independent of tumor cell-derived VEGF. ATG5 knockdown or chloroquine treatment inhibits both autophagy and KDR phosphorylation. 3D collagen scaffold VM assay, rapamycin/chloroquine treatment, ATG5 knockdown, ROS measurement, N-acetylcysteine treatment, KDR phosphorylation assay Autophagy Medium 28812437
2017 RCAN1.4 regulates agonist-stimulated VEGFR-2 internalization and establishment of endothelial cell polarity in response to VEGF; RCAN1.4 knockdown impairs VEGF-mediated cytoskeletal reorganization, directed cell migration, and sprouting angiogenesis. siRNA silencing, adenoviral overexpression, VEGFR-2 internalization assay, zebrafish morpholino knockdown, migration and sprouting assays Angiogenesis Medium 28271280
1998 VEGF-D is a ligand for both VEGFR-2 (Flk1/KDR) and VEGFR-3 (Flt4), can activate these receptors, and is a mitogen for endothelial cells; VEGF-D does not bind VEGFR-1. Receptor-binding capacity resides in the mature form of VEGF-D structurally related to VEGF-C. Receptor binding assays, endothelial cell mitogenesis assay, receptor activation assays Proceedings of the National Academy of Sciences of the United States of America High 9435229
2009 c-Cbl-mediated ubiquitination of PLCγ1 (a major VEGFR-2 signaling substrate) suppresses PLCγ1 tyrosine phosphorylation and VEGF-induced endothelial cell proliferation and angiogenesis. Loss of c-Cbl in mice results in enhanced retinal neovascularization and tumor-induced angiogenesis. c-Cbl knockout mice, ubiquitination assay, PLCγ1 phosphorylation assay, retinal neovascularization and tumor angiogenesis assays Biochemical Society transactions Medium 19909244

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. The Journal of cell biology 2167 12810700
2000 Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 1789 10648408
1998 Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 1687 9804796
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1992 Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochemical and biophysical research communications 1366 1417831
1994 Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. The Journal of biological chemistry 1298 7929439
2016 Mechanisms and regulation of endothelial VEGF receptor signalling. Nature reviews. Molecular cell biology 1179 27461391
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1999 Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1015 10428027
1998 Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proceedings of the National Academy of Sciences of the United States of America 989 9435229
2009 Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proceedings of the National Academy of Sciences of the United States of America 702 19372376
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2012 Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. Journal of biochemistry 623 23172303
2001 A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. The EMBO journal 618 11387210
2003 Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature medicine 614 12796773
2001 Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 540 11166270
2003 A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature medicine 535 12652295
2008 Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 533 18824714
1999 Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. The EMBO journal 533 10022831
2008 A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 515 18997771
1999 Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer research 482 9973224
1991 Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 477 1656371
1991 A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proceedings of the National Academy of Sciences of the United States of America 473 1717995
2010 Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 469 20048182
2012 VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer cell 465 22789536
2007 Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer cell 443 17222790
2003 TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 442 12887919
2006 Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. The Journal of cell biology 437 16893970
1996 Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. The Journal of biological chemistry 422 8621427
2014 Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 421 24529377
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
1999 Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. The Journal of biological chemistry 399 10455194
2000 Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. The Journal of clinical investigation 387 10953026
2002 VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. Journal of cellular biochemistry 368 11948691
1998 Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer metastasis reviews 279 9770111
2006 CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circulation research 278 16439688
2007 Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 192 17376891
2006 VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Frontiers in bioscience : a journal and virtual library 173 16146773
2012 CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood 161 22718841
2010 Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors. European journal of medicinal chemistry 139 20869793
2009 Functional significance of VEGFR-2 on ovarian cancer cells. International journal of cancer 133 19058181
2016 Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents. Scientific reports 132 27080011
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