{"gene":"KDR","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"Quantitative FRET, biochemical phosphorylation analysis, site-directed mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative FRET plus biochemical analysis plus mutagenesis in a single rigorous study; multiple orthogonal methods establishing dimerization mechanism","pmids":["27052508"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Isothermal titration calorimetry, small-angle X-ray scattering, X-ray crystallography","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution thermodynamics (ITC), SAXS structural modeling, and crystal structures in a single study; multiple orthogonal structural/biophysical methods","pmids":["22207738"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Bispecific synthetic ligand stimulation, phosphorylation assays, endothelial cell functional assays (migration, tube formation, proliferation), nitric oxide pathway analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — receptor-specific synthetic ligand with multiple orthogonal functional readouts in a single study; clearly delineates VEGFR-2 homodimer vs heterodimer functions","pmids":["22828632"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Structure-function analysis with progressive deletion mutants, pharmacological PKC inhibition, site-directed mutagenesis of serine residues, VEGFR-2 down-regulation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis combined with pharmacological and deletion approaches; multiple orthogonal methods establishing mechanism in single study","pmids":["15673613"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Chimeric receptor construction, site-directed mutagenesis, endothelial cell growth/migration/differentiation assays, PI3K activation assays","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis and chimeric receptor reconstitution; single lab, single publication","pmids":["12814952"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Mass spectrometry identification of methylation sites, site-directed mutagenesis, pharmacological methyltransferase inhibition, zebrafish angiogenesis assay, mouse tumor growth assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS identification, mutagenesis, pharmacological inhibition, and in vivo functional validation across two model organisms in one study","pmids":["24300896"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, VEGFR-2 phosphorylation assays, zebrafish and mouse angiogenesis models, protein aggregation assay","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated, multiple functional readouts including in vivo; single lab","pmids":["26059764"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assays, shRNA knockdown, overexpression, RING domain deletion mutants, cell surface VEGFR-2 measurement, endothelial proliferation and angiogenesis assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with ubiquitination assays and functional readouts; single lab","pmids":["26602861"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, pulldown, structural domain identification, siRNA knockdown, anti-CD146 antibody, conditional knockout mice, in vivo angiogenesis assay, tumor xenograft","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct molecular interaction, in vitro functional assays, and in vivo genetic knockout with multiple orthogonal approaches","pmids":["22718841"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, computational docking, mutagenesis, in vitro and in vivo angiogenesis assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction shown by Co-IP plus mutagenesis; single lab","pmids":["25825981"],"is_preprint":false},{"year":2007,"finding":"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.","method":"KDR deletion mutants, PI3K inhibition, antibody blockade of FLT-1, nuclear fractionation, in vitro wound healing assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutants plus pharmacological inhibition plus functional wound healing assay; single lab","pmids":["17382929"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation, NRP2 siRNA knockdown, NRP2 overexpression, endothelial cell survival and migration assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus gain/loss-of-function with functional readouts; single lab","pmids":["16621967"],"is_preprint":false},{"year":2006,"finding":"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.","method":"VEGFR-2 phosphorylation assays, VEGF binding affinity measurements, complex formation analysis, endothelial cell proliferation assays, VEGF165KF neuropilin-binding mutant","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — VEGF mutant analysis combined with binding affinity and phosphorylation assays; single lab","pmids":["17185751"],"is_preprint":false},{"year":2010,"finding":"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.","method":"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","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo requirement demonstrated, Co-IP complex identification, tyrosine phosphorylation assay, and pathway activation; multiple orthogonal methods in single study","pmids":["20434998"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Endothelial-specific conditional G13 knockout mice, VEGFR-2 promoter NF-κB binding site analysis, RhoA activation assays, rescue experiments with VEGFR-2 normalization","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with molecular mechanism (NF-κB binding site) and rescue experiment; multiple orthogonal approaches","pmids":["23664862"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Bisulfite sequencing, methylation-specific PCR (MSP), 5-Aza-2'deoxycytidine treatment, RT-PCR, Western blot","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bisulfite sequencing plus pharmacological demethylation rescue; single lab with two orthogonal methylation methods","pmids":["22251800"],"is_preprint":false},{"year":2017,"finding":"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.","method":"siRNA knockdown, adenoviral overexpression, VEGFR-2 internalization assay, zebrafish morpholino knockdown, endothelial migration and sprouting assays","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss and gain of function with in vitro and in vivo validation; single lab","pmids":["28271280"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Tunable hydrogel substrates, VEGFR-2 internalization assay, ROCK inhibition, ERK1/2 phosphorylation assay, cell proliferation assay, VEGFR-2 clustering analysis","journal":"Convergent science physical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological ROCK inhibition with multiple signaling/functional readouts; single lab","pmids":["29531793"],"is_preprint":false},{"year":2017,"finding":"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.","method":"3D collagen scaffold VM formation assay, rapamycin/chloroquine treatment, ATG5 siRNA knockdown, ROS measurement, N-acetylcysteine ROS inhibition, VEGFR-2 phosphorylation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition with multiple mechanistic readouts; single lab","pmids":["28812437"],"is_preprint":false},{"year":2008,"finding":"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.","method":"VEGFR-2 selective inhibitor (SU1498) treatment, cell cycle analysis, viability assays, pathway phosphorylation assays (MAPK, Akt, PKC)","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple signaling readouts; single lab","pmids":["18719373"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, Clp24 knockout mice, Vegfr2/Vegfr3 heterozygous genetic interaction (epistasis), zebrafish/Xenopus morpholino knockdown, CREB phosphorylation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct interaction by Co-IP, genetic epistasis in multiple organisms, and signaling readouts; multiple orthogonal methods","pmids":["20439428"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation (direct binding), VEGFR-2 phosphorylation assays, PI3K pathway phosphorylation analysis, endothelial cell functional assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding by Co-IP plus pathway analysis and functional assays; single lab","pmids":["24686084"],"is_preprint":false},{"year":2016,"finding":"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.","method":"CLEC14A knockout mice, VEGFR-2/VEGFR-3 expression and signaling assays, VEGFR-2 blockade rescue experiments, in vivo tumor angiogenesis assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with molecular mechanism and rescue; replicated across multiple functional readouts","pmids":["27991863"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor-selective antibody blockade replicated in vitro and in vivo, epistasis-like double-blockade experiments","pmids":["17210781"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Para-aortic splanchnopleural mesoderm coculture with OP9 stromal cells, soluble receptor competitor proteins (VEGFR-1-Fc, VEGFR-3-Fc), VEGFR-3-deficient mouse embryos","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus soluble receptor decoy epistasis; single lab","pmids":["11090062"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Vegfr2 heterozygous and conditional knockout mice, multiple independent tumor models, hematopoietic vs endothelial cell-specific deletion","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo gene dosage studies across three independent tumor models with cell-type-specific knockouts","pmids":["30283071"],"is_preprint":false},{"year":2000,"finding":"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.","method":"VEGFR-2 phosphorylation assay, proliferation assays, MMP-9 expression assay, migration through Matrigel, neutralizing antibody inhibition, human leukemia xenograft in NOD/SCID mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor phosphorylation, multiple functional assays, and in vivo xenograft validation with neutralizing antibody","pmids":["10953026"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Competitive binding assays (mAb vs VEGF on KDR), VEGF-induced signaling inhibition assays, endothelial cell mitogenesis assays, in vivo mouse tumor model with DC101","journal":"Cancer metastasis reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding plus signaling and cell functional assays, single lab","pmids":["9770111"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Genome-wide association study (GWAS) of sVEGFR-2 in healthy Amish volunteers, replication in cancer patients, pharmacodynamic analysis during pazopanib therapy","journal":"Clinical cancer research","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — GWAS identifies KDR variant associated with sVEGFR-2 levels; mechanistic interpretation of C482R is supported by functional FRET data from a separate paper but this paper itself is genetic association only","pmids":["25411163"],"is_preprint":false}],"current_model":"KDR/VEGFR-2 is a receptor tyrosine kinase that forms both pre-formed unliganded dimers (which are basally phosphorylated) and ligand-stabilized active dimers through a conformational change in the transmembrane domain; ligand binding to domains 2–3 drives receptor dimerization against an energetic barrier imposed by homotypic contacts in domains 4–7, and full activation requires lysine methylation at Lys1041 and PKC/serine-dependent carboxyl-tail regulation for down-regulation; VEGFR-2 signals through PI3K/Akt, MAPK/ERK, and PLC/PKC pathways to drive endothelial proliferation, migration, and angiogenesis, with its expression controlled transcriptionally by G13/RhoA/NF-κB and epigenetically by promoter DNA methylation, and with its cell-surface levels regulated by the ER E3 ligase RNF121 and agonist-induced clathrin/endocytic internalization; VEGFR-2 function is modulated by coreceptors CD146, EMMPRIN/CD147, neuropilins, and CLP24, and it can also form signaling-active heterodimers with VEGFR-1 that have distinct (non-proliferative) outputs; beyond angiogenesis, VEGFR-2 mediates axon growth in neurons downstream of Sema3E via the PlexinD1/NRP1 complex and supports odontoblast differentiation in dental pulp stem cells."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10953026","11090062"],"confidence":"High","gaps":["Did not resolve which downstream pathway dominates autocrine proliferation","Cross-talk with VEGFR-3 in normal vasculogenesis only inferred from deficient embryos"]},{"year":2003,"claim":"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","pmids":["12814952"],"confidence":"Medium","gaps":["Specific adaptors docking at each phosphotyrosine not identified","Single lab, single publication"]},{"year":2005,"claim":"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","pmids":["15673613"],"confidence":"High","gaps":["Identity of the responsible non-classical PKC isoform not pinned down","Kinase phosphorylating S1188/S1191 not established"]},{"year":2006,"claim":"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","pmids":["16621967","17185751"],"confidence":"Medium","gaps":["Structural basis of NRP1/2-VEGFR-2 coupling unresolved","Whether NRP1 vs NRP2 select different downstream outputs not addressed"]},{"year":2007,"claim":"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","pmids":["17382929"],"confidence":"Medium","gaps":["Function of nuclear KDR not defined","Trafficking route and cargo machinery only partially characterized"]},{"year":2010,"claim":"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","pmids":["20434998","20439428"],"confidence":"High","gaps":["How Sema3E activates VEGFR-2 kinase without VEGF is mechanistically unclear","CLP24 effect on CREB signaling not connected to canonical VEGFR-2 outputs"]},{"year":2011,"claim":"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","pmids":["27052508","22207738"],"confidence":"High","gaps":["Full-length receptor structure in membrane not solved","Exact residues mediating D4–7 homotypic contacts not enumerated"]},{"year":2012,"claim":"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","pmids":["22828632","22718841"],"confidence":"High","gaps":["Stoichiometry and physiological abundance of heterodimers in vivo unknown","How CD146 alters receptor conformation not defined"]},{"year":2013,"claim":"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","pmids":["24300896","23664862","17210781"],"confidence":"High","gaps":["Methyltransferase responsible for K1041 not identified","How methylation alters activation-loop dynamics structurally unresolved"]},{"year":2014,"claim":"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","pmids":["24686084","25411163"],"confidence":"Medium","gaps":["GABARBP physiological context single-lab only","rs34231037 mechanism is association-only in the GWAS itself"]},{"year":2015,"claim":"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","pmids":["26059764","26602861","25825981"],"confidence":"Medium","gaps":["Interplay between RNF121 ubiquitination and PDCL3 folding not integrated","Single-lab observations for each regulator"]},{"year":2017,"claim":"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","pmids":["28271280","29531793","28812437"],"confidence":"Medium","gaps":["Direct molecular link between ROS and KDR phosphorylation not defined","Single-lab, context-specific models"]},{"year":2018,"claim":"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","pmids":["30283071"],"confidence":"High","gaps":["Threshold of receptor abundance defining angiogenic competence not quantified","Why endothelial Fgfr1/2 deletion gave no synergy unexplained"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,26]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,26]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,23,25]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,10,16,17]}],"complexes":["VEGFR-2/VEGFR-1 heterodimer","VEGFR-2/PlexinD1/NRP1 complex"],"partners":["FLT1","CD146","BSG","NRP1","NRP2","PDCL3","RNF121","PLXND1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35968","full_name":"Vascular endothelial growth factor receptor 2","aliases":["Fetal liver kinase 1","FLK-1","Kinase insert domain receptor","KDR","Protein-tyrosine kinase receptor flk-1"],"length_aa":1356,"mass_kda":151.5,"function":"Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. 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chemotherapeutic agents based on the quinolone-3-carboxamide scaffold acting by VEGFR-2 inhibition.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37443185","citation_count":17,"is_preprint":false},{"pmid":"25499009","id":"PMC_25499009","title":"2-Methoxyestradiol regulates VEGFR-2 and sFlt-1 expression in human placenta.","date":"2014","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/25499009","citation_count":16,"is_preprint":false},{"pmid":"26602861","id":"PMC_26602861","title":"RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR-2.","date":"2015","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/26602861","citation_count":16,"is_preprint":false},{"pmid":"25818819","id":"PMC_25818819","title":"CD144, CD146 and VEGFR-2 properly identify circulating endothelial cell.","date":"2015","source":"Revista brasileira de hematologia e hemoterapia","url":"https://pubmed.ncbi.nlm.nih.gov/25818819","citation_count":16,"is_preprint":false},{"pmid":"37261471","id":"PMC_37261471","title":"Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/37261471","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54851,"output_tokens":8942,"usd":0.149341,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18692,"output_tokens":5022,"usd":0.109505,"stage2_stop_reason":"end_turn"},"total_usd":0.258846,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative FRET, biochemical phosphorylation analysis, site-directed mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative FRET plus biochemical analysis plus mutagenesis in a single rigorous study; multiple orthogonal methods establishing dimerization mechanism\",\n      \"pmids\": [\"27052508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Isothermal titration calorimetry, small-angle X-ray scattering, X-ray crystallography\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution thermodynamics (ITC), SAXS structural modeling, and crystal structures in a single study; multiple orthogonal structural/biophysical methods\",\n      \"pmids\": [\"22207738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Bispecific synthetic ligand stimulation, phosphorylation assays, endothelial cell functional assays (migration, tube formation, proliferation), nitric oxide pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — receptor-specific synthetic ligand with multiple orthogonal functional readouts in a single study; clearly delineates VEGFR-2 homodimer vs heterodimer functions\",\n      \"pmids\": [\"22828632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Structure-function analysis with progressive deletion mutants, pharmacological PKC inhibition, site-directed mutagenesis of serine residues, VEGFR-2 down-regulation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis combined with pharmacological and deletion approaches; multiple orthogonal methods establishing mechanism in single study\",\n      \"pmids\": [\"15673613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Chimeric receptor construction, site-directed mutagenesis, endothelial cell growth/migration/differentiation assays, PI3K activation assays\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis and chimeric receptor reconstitution; single lab, single publication\",\n      \"pmids\": [\"12814952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry identification of methylation sites, site-directed mutagenesis, pharmacological methyltransferase inhibition, zebrafish angiogenesis assay, mouse tumor growth assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS identification, mutagenesis, pharmacological inhibition, and in vivo functional validation across two model organisms in one study\",\n      \"pmids\": [\"24300896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, VEGFR-2 phosphorylation assays, zebrafish and mouse angiogenesis models, protein aggregation assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated, multiple functional readouts including in vivo; single lab\",\n      \"pmids\": [\"26059764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, shRNA knockdown, overexpression, RING domain deletion mutants, cell surface VEGFR-2 measurement, endothelial proliferation and angiogenesis assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with ubiquitination assays and functional readouts; single lab\",\n      \"pmids\": [\"26602861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, structural domain identification, siRNA knockdown, anti-CD146 antibody, conditional knockout mice, in vivo angiogenesis assay, tumor xenograft\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct molecular interaction, in vitro functional assays, and in vivo genetic knockout with multiple orthogonal approaches\",\n      \"pmids\": [\"22718841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, computational docking, mutagenesis, in vitro and in vivo angiogenesis assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown by Co-IP plus mutagenesis; single lab\",\n      \"pmids\": [\"25825981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"KDR deletion mutants, PI3K inhibition, antibody blockade of FLT-1, nuclear fractionation, in vitro wound healing assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutants plus pharmacological inhibition plus functional wound healing assay; single lab\",\n      \"pmids\": [\"17382929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, NRP2 siRNA knockdown, NRP2 overexpression, endothelial cell survival and migration assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus gain/loss-of-function with functional readouts; single lab\",\n      \"pmids\": [\"16621967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"VEGFR-2 phosphorylation assays, VEGF binding affinity measurements, complex formation analysis, endothelial cell proliferation assays, VEGF165KF neuropilin-binding mutant\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — VEGF mutant analysis combined with binding affinity and phosphorylation assays; single lab\",\n      \"pmids\": [\"17185751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo requirement demonstrated, Co-IP complex identification, tyrosine phosphorylation assay, and pathway activation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"20434998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Endothelial-specific conditional G13 knockout mice, VEGFR-2 promoter NF-κB binding site analysis, RhoA activation assays, rescue experiments with VEGFR-2 normalization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with molecular mechanism (NF-κB binding site) and rescue experiment; multiple orthogonal approaches\",\n      \"pmids\": [\"23664862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Bisulfite sequencing, methylation-specific PCR (MSP), 5-Aza-2'deoxycytidine treatment, RT-PCR, Western blot\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bisulfite sequencing plus pharmacological demethylation rescue; single lab with two orthogonal methylation methods\",\n      \"pmids\": [\"22251800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, adenoviral overexpression, VEGFR-2 internalization assay, zebrafish morpholino knockdown, endothelial migration and sprouting assays\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss and gain of function with in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"28271280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Tunable hydrogel substrates, VEGFR-2 internalization assay, ROCK inhibition, ERK1/2 phosphorylation assay, cell proliferation assay, VEGFR-2 clustering analysis\",\n      \"journal\": \"Convergent science physical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological ROCK inhibition with multiple signaling/functional readouts; single lab\",\n      \"pmids\": [\"29531793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"3D collagen scaffold VM formation assay, rapamycin/chloroquine treatment, ATG5 siRNA knockdown, ROS measurement, N-acetylcysteine ROS inhibition, VEGFR-2 phosphorylation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition with multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"28812437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"VEGFR-2 selective inhibitor (SU1498) treatment, cell cycle analysis, viability assays, pathway phosphorylation assays (MAPK, Akt, PKC)\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple signaling readouts; single lab\",\n      \"pmids\": [\"18719373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Clp24 knockout mice, Vegfr2/Vegfr3 heterozygous genetic interaction (epistasis), zebrafish/Xenopus morpholino knockdown, CREB phosphorylation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct interaction by Co-IP, genetic epistasis in multiple organisms, and signaling readouts; multiple orthogonal methods\",\n      \"pmids\": [\"20439428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (direct binding), VEGFR-2 phosphorylation assays, PI3K pathway phosphorylation analysis, endothelial cell functional assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by Co-IP plus pathway analysis and functional assays; single lab\",\n      \"pmids\": [\"24686084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"CLEC14A knockout mice, VEGFR-2/VEGFR-3 expression and signaling assays, VEGFR-2 blockade rescue experiments, in vivo tumor angiogenesis assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with molecular mechanism and rescue; replicated across multiple functional readouts\",\n      \"pmids\": [\"27991863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor-selective antibody blockade replicated in vitro and in vivo, epistasis-like double-blockade experiments\",\n      \"pmids\": [\"17210781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Para-aortic splanchnopleural mesoderm coculture with OP9 stromal cells, soluble receptor competitor proteins (VEGFR-1-Fc, VEGFR-3-Fc), VEGFR-3-deficient mouse embryos\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus soluble receptor decoy epistasis; single lab\",\n      \"pmids\": [\"11090062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Vegfr2 heterozygous and conditional knockout mice, multiple independent tumor models, hematopoietic vs endothelial cell-specific deletion\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo gene dosage studies across three independent tumor models with cell-type-specific knockouts\",\n      \"pmids\": [\"30283071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"VEGFR-2 phosphorylation assay, proliferation assays, MMP-9 expression assay, migration through Matrigel, neutralizing antibody inhibition, human leukemia xenograft in NOD/SCID mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor phosphorylation, multiple functional assays, and in vivo xenograft validation with neutralizing antibody\",\n      \"pmids\": [\"10953026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Competitive binding assays (mAb vs VEGF on KDR), VEGF-induced signaling inhibition assays, endothelial cell mitogenesis assays, in vivo mouse tumor model with DC101\",\n      \"journal\": \"Cancer metastasis reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding plus signaling and cell functional assays, single lab\",\n      \"pmids\": [\"9770111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide association study (GWAS) of sVEGFR-2 in healthy Amish volunteers, replication in cancer patients, pharmacodynamic analysis during pazopanib therapy\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — GWAS identifies KDR variant associated with sVEGFR-2 levels; mechanistic interpretation of C482R is supported by functional FRET data from a separate paper but this paper itself is genetic association only\",\n      \"pmids\": [\"25411163\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDR/VEGFR-2 is a receptor tyrosine kinase that forms both pre-formed unliganded dimers (which are basally phosphorylated) and ligand-stabilized active dimers through a conformational change in the transmembrane domain; ligand binding to domains 2–3 drives receptor dimerization against an energetic barrier imposed by homotypic contacts in domains 4–7, and full activation requires lysine methylation at Lys1041 and PKC/serine-dependent carboxyl-tail regulation for down-regulation; VEGFR-2 signals through PI3K/Akt, MAPK/ERK, and PLC/PKC pathways to drive endothelial proliferation, migration, and angiogenesis, with its expression controlled transcriptionally by G13/RhoA/NF-κB and epigenetically by promoter DNA methylation, and with its cell-surface levels regulated by the ER E3 ligase RNF121 and agonist-induced clathrin/endocytic internalization; VEGFR-2 function is modulated by coreceptors CD146, EMMPRIN/CD147, neuropilins, and CLP24, and it can also form signaling-active heterodimers with VEGFR-1 that have distinct (non-proliferative) outputs; beyond angiogenesis, VEGFR-2 mediates axon growth in neurons downstream of Sema3E via the PlexinD1/NRP1 complex and supports odontoblast differentiation in dental pulp stem cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDR (VEGFR-2) is a receptor tyrosine kinase that serves as the principal endothelial transducer of VEGF signals driving vascular proliferation, migration, and angiogenesis [#25, #26]. It exists as pre-formed unliganded dimers that are basally phosphorylated, with ligand binding to extracellular domains 2\\u20133 inducing a transmembrane-domain conformational change that boosts kinase activation; energetically unfavorable homotypic contacts in domains 4\\u20137 enforce monomer re-orientation and suppress ligand-independent firing, and the pathogenic C482R mutant bypasses this restraint by mimicking the ligand-bound dimer [#0, #1]. 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 [#4, #5]. Productive signaling proceeds through PI3K/Akt, MAPK/ERK, and PLC/PKC arms to control endothelial proliferation, survival, and cell-cycle progression [#19, #4]. 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 [#8, #9, #11, #12]; heterodimers with VEGFR-1 yield migration and vasorelaxation without proliferation [#2]; and CLP24 and CLEC14A balance VEGFR-2 against VEGFR-3 in lymphatic and vascular development [#20, #22]. Receptor abundance and surface levels are regulated transcriptionally by G13/RhoA/NF-\\u03baB 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 [#14, #15, #6, #7, #3, #10]. Beyond angiogenesis, VEGFR-2 mediates Sema3E-driven axonal growth in neurons via a PlexinD1/NRP1 complex independent of VEGF ligands [#13], and a germline C482R variant accounts for a substantial fraction of serum soluble VEGFR-2 variance [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"VEGF165 phosphorylation, proliferation/migration assays, neutralizing anti-KDR mAb, and leukemia xenografts; plus VEGF-C/VEGFR-2 epistasis in mouse embryos\",\n      \"pmids\": [\"10953026\", \"11090062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which downstream pathway dominates autocrine proliferation\", \"Cross-talk with VEGFR-3 in normal vasculogenesis only inferred from deficient embryos\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped intracellular tyrosines required for VEGFR-2-specific endothelial growth and PI3K activation, distinguishing its signaling from VEGFR-1.\",\n      \"evidence\": \"Chimeric CSF-1R/VEGFR-2 receptors and site-directed mutagenesis of Y799, Y1173, Y1212 with endothelial functional and PI3K assays\",\n      \"pmids\": [\"12814952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific adaptors docking at each phosphotyrosine not identified\", \"Single lab, single publication\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the carboxyl-tail and PKC-dependent machinery that down-regulates the receptor, showing c-Cbl phosphorylates but does not ubiquitinate VEGFR-2.\",\n      \"evidence\": \"Progressive deletion mutants, S1188/S1191 mutagenesis, and pharmacological PKC inhibition with down-regulation assays\",\n      \"pmids\": [\"15673613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible non-classical PKC isoform not pinned down\", \"Kinase phosphorylating S1188/S1191 not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed neuropilins act as coreceptors that raise VEGFR-2 phosphorylation threshold and ligand affinity, including for non-neuropilin-binding VEGF121, via pre-formed complexes.\",\n      \"evidence\": \"Co-IP, NRP siRNA/overexpression, VEGF binding-affinity and phosphorylation assays, VEGF165 neuropilin-binding mutant\",\n      \"pmids\": [\"16621967\", \"17185751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NRP1/2-VEGFR-2 coupling unresolved\", \"Whether NRP1 vs NRP2 select different downstream outputs not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked VEGFR-2 internalization to nuclear trafficking dependent on FLT-1, PI3K/AKT, and receptor phosphorylation as a requirement for endothelial monolayer repair.\",\n      \"evidence\": \"KDR tyrosine deletion mutants, PI3K inhibition, FLT-1 antibody blockade, nuclear fractionation, in vitro wound healing\",\n      \"pmids\": [\"17382929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of nuclear KDR not defined\", \"Trafficking route and cargo machinery only partially characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a VEGF-independent neuronal role: VEGFR-2 transduces Sema3E via a PlexinD1/NRP1 complex to drive axonal growth through PI3K/Akt.\",\n      \"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\",\n      \"pmids\": [\"20434998\", \"20439428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Sema3E activates VEGFR-2 kinase without VEGF is mechanistically unclear\", \"CLP24 effect on CREB signaling not connected to canonical VEGFR-2 outputs\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the activation mechanism: pre-formed basally phosphorylated dimers activated by a transmembrane conformational change, restrained by unfavorable D4\\u20137 contacts, with C482R mimicking the active conformation.\",\n      \"evidence\": \"Quantitative FRET, phosphorylation analysis, mutagenesis; ITC, SAXS, and crystal structures of VEGF-A/E with domains D23\",\n      \"pmids\": [\"27052508\", \"22207738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor structure in membrane not solved\", \"Exact residues mediating D4\\u20137 homotypic contacts not enumerated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished VEGFR-1/VEGFR-2 heterodimer outputs (migration, vasorelaxation, no proliferation) from homodimers, and identified CD146 as a required coreceptor for VEGFR-2 activation.\",\n      \"evidence\": \"Bispecific synthetic ligand with functional readouts; CD146 Co-IP/pulldown, siRNA, antibody, and endothelial-specific KO mice\",\n      \"pmids\": [\"22828632\", \"22718841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and physiological abundance of heterodimers in vivo unknown\", \"How CD146 alters receptor conformation not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed Lys1041 methylation is a constitutive, ligand-independent enhancer of kinase activity required for angiogenesis, and that G13/RhoA/NF-\\u03baB transcriptionally sets VEGFR-2 levels for angiogenic responsiveness; VEGFR-2 cooperates with VEGFR-3 in lymphangiogenesis.\",\n      \"evidence\": \"MS site mapping, K1041 mutagenesis, methyltransferase inhibition with zebrafish/mouse models; endothelial G13 conditional KO with NF-\\u03baB promoter site and rescue; receptor-selective antibody double-blockade in lymphatics\",\n      \"pmids\": [\"24300896\", \"23664862\", \"17210781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferase responsible for K1041 not identified\", \"How methylation alters activation-loop dynamics structurally unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterized post-translational and direct-binding regulators of VEGFR-2 activity and linked the C482R germline variant to circulating soluble VEGFR-2 levels.\",\n      \"evidence\": \"GABARBP Co-IP and PI3K-pathway/functional assays; GWAS of sVEGFR-2 with pazopanib pharmacodynamics\",\n      \"pmids\": [\"24686084\", \"25411163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GABARBP physiological context single-lab only\", \"rs34231037 mechanism is association-only in the GWAS itself\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined biosynthetic quality control of VEGFR-2 through the chaperone PDCL3 and ER E3 ligase RNF121, plus EMMPRIN/CD147 as an extracellular coreceptor.\",\n      \"evidence\": \"Co-IP, siRNA/shRNA and overexpression, ubiquitination assays, RING-domain mutants, and in vivo angiogenesis; EMMPRIN docking and mutagenesis\",\n      \"pmids\": [\"26059764\", \"26602861\", \"25825981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between RNF121 ubiquitination and PDCL3 folding not integrated\", \"Single-lab observations for each regulator\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA/adenoviral RCAN1.4 with zebrafish; tunable hydrogels and ROCK inhibition; glioma-stem-cell autophagy modulation with ATG5 knockdown and ROS measurement\",\n      \"pmids\": [\"28271280\", \"29531793\", \"28812437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between ROS and KDR phosphorylation not defined\", \"Single-lab, context-specific models\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that endothelial Vegfr2 gene dosage, not hematopoietic expression, is the critical determinant of tumor angiogenesis and growth.\",\n      \"evidence\": \"Vegfr2 heterozygous and cell-type-specific conditional KO mice across three independent tumor models\",\n      \"pmids\": [\"30283071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of receptor abundance defining angiogenic competence not quantified\", \"Why endothelial Fgfr1/2 deletion gave no synergy unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzyme identified for K1041 methylation\", \"No unifying model linking coreceptors, dimer state, and pathway selection\", \"Function of nuclear-localized VEGFR-2 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 26]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 26]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 23, 25]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 10, 16, 17]}\n    ],\n    \"complexes\": [\n      \"VEGFR-2/VEGFR-1 heterodimer\",\n      \"VEGFR-2/PlexinD1/NRP1 complex\"\n    ],\n    \"partners\": [\n      \"FLT1\",\n      \"CD146\",\n      \"BSG\",\n      \"NRP1\",\n      \"NRP2\",\n      \"PDCL3\",\n      \"RNF121\",\n      \"PLXND1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}