Affinage

FLT4

Vascular endothelial growth factor receptor 3 · UniProt P35916

Length
1363 aa
Mass
152.8 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLT4/VEGFR3 is a class III receptor tyrosine kinase, structurally related to FLT1 and KDR, that drives lymphatic and vascular endothelial development by transducing signals from the proteolytically processed ligands VEGF-C and VEGF-D (PMID:1327515, PMID:8386825, PMID:9247316, PMID:9435229). Unlike VEGF-A, these ligands induce receptor autophosphorylation, and the activated kinase couples to SHC/GRB2 adaptors to engage downstream signaling (PMID:7970715, PMID:9247316). VEGFR3 bifurcates its output: VEGFR3 homodimers activate ERK1/2, while VEGF-C-driven AKT activation requires a VEGFR3/VEGFR2 heterodimer dependent on neuropilin-1, with VE-PTP restraining both arms (PMID:25524775). Its ligand-binding and kinase activities are required for lymphangiogenesis but not angiogenesis, and its kinase activity supports lymphatic vessel maintenance and chylomicron uptake by intestinal lacteals (PMID:20697430, PMID:25561555, PMID:30618798). VEGFR3 also negatively modulates VEGFR2: by sequestering VEGF-C and by limiting VEGFR2 protein levels, VEGFR3 preserves VE-cadherin junctions and restrains vascular permeability in quiescent endothelium (PMID:11090062, PMID:28298294). VEGFR3 and Notch operate in reciprocal feedback—Notch suppresses VEGFR3 expression while VEGFR3 promotes NOTCH1-dependent button junction formation in lymphatic capillaries, and mosaic loss of VEGFR3 drives non-cell-autonomous hyperplasia through reduced Notch signaling (PMID:22426001, PMID:29615616, PMID:37454290). Surface availability of VEGFR3 is tightly controlled by Ang2/Tie/PI3K-AKT signaling and by epsin-mediated Golgi degradation, while its transcription is governed by sumoylated Prox1, Tbx1, and mitochondrial complex III-dependent histone modifications at the Vegfr3 locus (PMID:19706680, PMID:20439995, PMID:30102256, PMID:33931446, PMID:35763346). Beyond endothelium, VEGFR3 is expressed on macrophages and dendritic cells, where it directs lymphangiogenesis and, in infected macrophages, phosphorylates AMPK-α to coordinate glycolytic reprogramming, autophagy, and inflammasome suppression (PMID:12819011, PMID:27783948, PMID:34632918). Loss-of-function VEGFR3 mutations cause primary congenital lymphedema (PMID:19289394).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1992 High

    Established FLT4 as a transmembrane receptor tyrosine kinase belonging to the VEGFR/class III subfamily, defining its molecular identity before any ligand or function was known.

    Evidence cDNA cloning, sequencing, and structural analysis; chromosomal mapping

    PMID:1310071 PMID:1319394 PMID:1327515 PMID:8386825

    Open questions at the time
    • No ligand identified
    • No functional or signaling role established
  2. 1993 Medium

    Localized FLT4 expression to vascular endothelium of developing vessels and revealed isoform diversity, hinting at a developmental vascular role and tail-dependent functional variation.

    Evidence In situ hybridization in fetal tissues; cDNA/genomic analysis of two C-terminal isoforms; biochemical characterization of the ~170 kDa glycoprotein

    PMID:7692369 PMID:8245783 PMID:8386825

    Open questions at the time
    • Functional difference between isoforms not yet tested
    • Signaling output unknown
  3. 1994 High

    Showed FLT4 does not respond to VEGF-A and, using a chimeric receptor, that its activated kinase couples to SHC/GRB2 adaptors, distinguishing it from FLT1/KDR and defining its proximal signaling.

    Evidence CSF-1R/FLT4 chimera, SH2-domain binding assays, autophosphorylation and thymidine incorporation assays

    PMID:7970715

    Open questions at the time
    • Cognate ligand not identified
    • Chimera does not establish native ligand-dependent signaling
  4. 1995 Medium

    Demonstrated the long FLT4 isoform confers transforming potential, linking C-terminal tail differences to distinct biological outputs.

    Evidence Soft agar colony assay with CSF-1R/FLT4 chimeras in Rat-2 cells

    PMID:7898938

    Open questions at the time
    • Relies on chimeric receptor not native ligand
    • Mechanism of isoform-specific transformation unresolved
  5. 1997 High

    Identified VEGF-C as the cognate ligand activating FLT4 and mapped a downstream Shc/Grb2/SOS, RAFTK, JNK and paxillin signaling complex, converting the orphan receptor into a defined lymphatic mitogenic pathway.

    Evidence BIAcore binding, affinity chromatography, phosphorylation and mitogenesis assays; co-IP and kinase assays in HEL cells

    PMID:9247316 PMID:9345034

    Open questions at the time
    • Second ligand and receptor heterodimerization not yet addressed
    • In vivo lymphatic role not yet tested
  6. 1998 High

    Defined VEGF-D as a second ligand shared with VEGFR-2, broadening the receptor's ligand repertoire and foreshadowing VEGFR2/VEGFR3 crosstalk.

    Evidence Receptor-binding and activation assays with deletion mutants

    PMID:9435229

    Open questions at the time
    • Functional consequences of dual-receptor binding unclear
    • No structural model of ligand-receptor engagement
  7. 2000 High

    Revealed that VEGFR3 controls VEGFR2 signaling by sequestering VEGF-C, establishing the first inter-receptor regulatory mechanism.

    Evidence P-Sp/OP9 coculture, VEGFR3-deficient mouse embryos, soluble receptor competition

    PMID:11090062

    Open questions at the time
    • Molecular basis of crosstalk (heterodimer vs. ligand competition) not separated
    • Adult vascular consequences untested
  8. 2001 Medium

    Characterized the VEGFR3 promoter as a TATA-less endothelial-specific element, opening study of its transcriptional control.

    Evidence Reporter transfection and transgenic mouse promoter assays

    PMID:11292664

    Open questions at the time
    • Trans-acting factors not identified
    • Weak lymphatic activity suggests missing enhancers
  9. 2002 Medium

    Showed VEGFR3 negatively modulates VEGFR2 activity to maintain vascular integrity, extending its regulatory role to endothelial behavior.

    Evidence Antagonistic VEGFR3 antibody (AFL4) in ES-derived endothelial cultures with cytological analysis

    PMID:12393458

    Open questions at the time
    • Antibody mechanism (block vs. activate) ambiguous
    • In vivo permeability link not established
  10. 2003 Medium

    Documented VEGFR3 expression on immature dendritic cells, the first evidence of a non-endothelial functional compartment.

    Evidence Immunofluorescence and flow cytometry of corneal dendritic cells

    PMID:12819011

    Open questions at the time
    • Function of VEGFR3 on DCs not defined
    • Signaling in myeloid cells unaddressed
  11. 2009 High

    Connected VEGFR3 to transcriptional and developmental control circuits, showing Prox1 sumoylation drives VEGFR3 expression, Dll4/Notch restrains Vegfc/Flt4 angiogenic responses, and a human kinase-domain mutation causes recessive lymphedema.

    Evidence In vitro sumoylation and reporter assays; zebrafish forward genetics and epistasis; patient mutation functional assays

    PMID:19289394 PMID:19706680 PMID:19906867

    Open questions at the time
    • Mechanism coupling Notch to VEGFR3 expression not yet defined
    • Allelic spectrum of human disease incomplete
  12. 2010 High

    Separated VEGFR3 requirements for lymphangiogenesis versus angiogenesis and showed kinase-independent heterodimer suppression of VEGFR2, and identified Tbx1 as a direct transcriptional activator of Vegfr3.

    Evidence Conditional knock-in mice (ligand-binding-deletion and kinase-dead); co-IP heterodimer detection; ChIP and conditional Tbx1 knockout

    PMID:20439995 PMID:20697430

    Open questions at the time
    • Structural basis of heterodimer-mediated VEGFR2 suppression unknown
    • Other enhancer-binding factors not catalogued
  13. 2011 High

    Placed Vegfc/Vegfr3 downstream of Rspo1/Wnt signaling, embedding the receptor in a defined upstream developmental cascade.

    Evidence Zebrafish forward genetics, morpholino knockdown, endothelial-autonomous Wnt inhibition, epistasis

    PMID:22007135

    Open questions at the time
    • Direct vs. indirect Wnt-to-Vegfc link not resolved
    • Mammalian conservation untested in this study
  14. 2012 High

    Defined a Notch–VEGFR3 feedback loop and ligand-independent VEGFR3 kinase signaling, and identified miR-1236 as a post-transcriptional brake, refining the control of endothelial sprouting.

    Evidence Inducible Notch loss-of-function with pharmacological/antibody dissection in retina; 3'UTR luciferase and miRNA overexpression in LECs

    PMID:22223733 PMID:22426001

    Open questions at the time
    • Mechanism of ligand-independent kinase activation undefined
    • Physiological miR-1236 regulation not established in vivo
  15. 2014 High

    Dissected the VEGFR3 signaling bifurcation—ERK via homodimers, AKT via NRP1-dependent VEGFR2 heterodimers—and identified mechanotransductive control through ILK/β1-integrin.

    Evidence Co-IP, siRNA silencing, phosphorylation assays in LECs; endothelial-specific ILK knockout with Itgb1 genetic rescue

    PMID:25524775 PMID:30518533

    Open questions at the time
    • Structural geometry of the homodimer vs heterodimer outputs not resolved
    • How β1 integrin hyperactivates VEGFR3 mechanistically unclear
  16. 2015 High

    Genetically separated VEGFR2 and VEGFR3 requirements, fixing VEGFR3 as essential for lymphangiogenesis and lymphatic maintenance but dispensable for retinal angiogenesis.

    Evidence Conditional double knockouts in mice with Notch inhibition and retinal phenotyping

    PMID:25561555

    Open questions at the time
    • Context-dependence of VEGFR3 angiogenic contribution not fully mapped
  17. 2016 Medium

    Established a tumor-promoting role for VEGFR3 on macrophages, where VEGF-C/VEGFR3 drives lymphangiogenesis and pro-metastatic activity.

    Evidence VEGFR3 blockade and macrophage transfer in murine tumor models

    PMID:27783948

    Open questions at the time
    • Macrophage-intrinsic VEGFR3 signaling not defined
    • Single-lab tumor model
  18. 2017 High

    Showed VEGFR3 limits VEGFR2 protein levels to protect endothelial junctions and restrain permeability, with VEGFR2 co-deletion rescuing the phenotype.

    Evidence Conditional Vegfr3 deletion, EC siRNA, VEGFR2 phosphorylation and VE-cadherin assays, Vegfr2 co-deletion rescue

    PMID:28298294

    Open questions at the time
    • Mechanism by which VEGFR3 limits VEGFR2 abundance unknown
    • Relation to ligand-sequestration model not unified
  19. 2018 High

    Uncovered multiple layers of VEGFR3 surface and activity control—epsin-mediated Golgi degradation in diabetes, CLEC14A and uPARAP complexes balancing VEGFR2/VEGFR3, non-cell-autonomous Notch-dependent hyperplasia, and a chylomicron-absorption role.

    Evidence Lymphatic epsin double KO and degradation assays; CLEC14A and uPARAP co-IP and KO; mosaic Vegfr3 deletion with Notch readouts; Chy kinase-dead mouse lipid assays

    PMID:27991863 PMID:29615616 PMID:30102256 PMID:30518756 PMID:30618798

    Open questions at the time
    • Whether these regulators converge on a single trafficking node is unclear
    • uPARAP/CLEC14A direct binding interfaces undefined
  20. 2021 Medium

    Expanded VEGFR3 outputs to direct AMPK phosphorylation in macrophages for antibacterial defense, ERK-driven cell-cycle arrest in endothelial precursors, and a mitochondrial complex III–chromatin axis sustaining Vegfr3 expression.

    Evidence FLT4 mutant macrophage AMPK phosphorylation/autophagy/metabolomics assays; zebrafish cell-cycle reporters; LEC complex III conditional KO with histone-mark ChIP

    PMID:33931446 PMID:34133928 PMID:34632918

    Open questions at the time
    • Direct AMPK phosphorylation needs structural/kinetic confirmation
    • Single-lab findings for each mechanism
  21. 2022 High

    Defined an Ang2/Tie/PI3K-AKT requirement for cell-surface presentation of VEGFR3, linking angiopoietin signaling to receptor availability.

    Evidence Tie1, Tie2, Ang2, PI3K-p110α deletions and Ang2-blocking antibody with VEGFR3 surface assays across neonatal and adult models

    PMID:35763346

    Open questions at the time
    • Molecular step linking AKT to VEGFR3 trafficking unidentified
  22. 2023 High

    Established VEGFR3 control of NOTCH1-dependent button junction formation, a dural-lymphatic role separable from CNS autoimmunity, and a neuroprotective VEGF-C/VEGFR3 axis on CNS macrophages.

    Evidence Lymphatic-specific Flt4 KO with NOTCH1-ICD rescue; three VEGFR3-inhibition strategies in EAE; myeloid Vegfr3ΔLBD model in JEV encephalitis

    PMID:37058549 PMID:37167063 PMID:37454290

    Open questions at the time
    • How VEGFR3 induces NOTCH1 expression mechanistically unresolved
    • Macrophage VEGFR3 signaling pathway to TNF-α suppression undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VEGFR3 toggles between ligand-dependent and ligand-independent signaling, and the unified structural/trafficking logic that integrates VEGFR2 crosstalk, Notch feedback, and surface-expression control, remains unresolved.
  • No structural model of the VEGFR3 homodimer vs VEGFR2 heterodimer signaling states
  • Mechanism of ligand-independent kinase activation undefined
  • Convergence point of the multiple surface/abundance regulators unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 1
Partners
CLEC14AGRB2ITGB1KDRNRP1PRKAASHCUPARAP
Complex memberships
VEGFR3/CLEC14A complexVEGFR3/VEGFR2 heterodimerVEGFR3/uPARAP/VEGFR2 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 FLT4 encodes a transmembrane receptor tyrosine kinase with seven immunoglobulin-like loops in its extracellular domain, structurally related to FLT1 and KDR/FLK1, constituting a subfamily of class III tyrosine kinases. cDNA cloning, sequencing, structural analysis Cancer research High 1327515 8386825
1992 FLT4 gene maps to chromosomal region 5q33-qter (human) and chromosome 11 (mouse). Chromosomal mapping, genomic analysis Cancer research / Genomics High 1310071 1319394
1993 FLT4 protein is expressed as a ~170 kDa glycoprotein when transiently expressed in Cos-7 cells, as shown by immunoprecipitation with FLT4-specific antisera. Transient expression in Cos-7 cells, immunoprecipitation, Western blot Oncogene Medium 8386825
1993 FLT4 is expressed in vascular endothelial cells of developing vessels in multiple fetal organs, with overlapping but distinct expression patterns compared to FLT1 and KDR/FLK1. Northern blot, in situ hybridization in human fetal tissues The Journal of experimental medicine Medium 8245783
1993 Two FLT4 isoforms (short and long) are generated by alternative polyadenylation and subsequent alternative splicing, producing proteins differing in their C-terminal tails. cDNA cloning, genomic structure analysis, Northern blot Oncogene High 7692369
1994 FLT4 does not bind VEGF and does not undergo autophosphorylation in response to VEGF. When its tyrosine kinase domain was activated via a CSF-1R/FLT4 chimera, FLT4 kinase interacted with SHC and GRB2 adaptor proteins via their SH2 domains in vitro and with SHC in cells, and stimulated thymidine incorporation in NIH3T3 fibroblasts but not in endothelial cells. Receptor chimera assay, SH2 domain binding assay, autophosphorylation assay, thymidine incorporation Oncogene High 7970715
1995 The long isoform of FLT4 (FF4L), but not the short isoform (FF4S), can induce anchorage-independent growth of Rat-2 cells in soft agar upon CSF-1 stimulation of CSF-1R/FLT4 chimeras, demonstrating functional differences between the two isoforms. Both isoforms are highly glycosylated (~180 kDa) cell-surface kinases. Soft agar colony assay, CSF-1R/FLT4 chimeric receptor expression, biochemical characterization Oncogene Medium 7898938
1997 VEGF-C (Flt4 ligand/VRP) is the cognate ligand for FLT4; recombinant VEGF-C activates FLT4 as demonstrated by induction of tyrosyl phosphorylation and stimulates mitogenesis of lymphatic endothelial cells. VEGF-C is proteolytically processed to generate a mature ~21 kDa homodimer. BIAcore binding assay, receptor affinity chromatography, tyrosyl phosphorylation assay, mitogenesis assay Oncogene High 9247316
1997 VRP/VEGF-C stimulation of FLT4 in hematopoietic HEL cells induces formation of a signaling complex including Shc, Grb2, and SOS at the activated receptor, activates RAFTK (focal adhesion kinase family member) and its association with Grb2, activates JNK, and induces paxillin phosphorylation. Co-immunoprecipitation, kinase assay, Western blot for phosphorylation Blood Medium 9345034
1998 VEGF-D is a ligand for both VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors; the receptor-binding capacity resides in the VEGF-homology domain (mature form). VEGF-D does not bind VEGFR-1. Receptor-binding assays, receptor activation assays, deletion mutant analysis Proceedings of the National Academy of Sciences High 9435229
2000 VEGF-C signaling through VEGFR-3 regulates VEGFR-2 signaling: in VEGFR-3-deficient embryos, excess VEGF-C signals through VEGFR-2, causing disturbed vasculogenesis and suppressed hematopoiesis. VEGFR-3 binding of VEGF-C limits the amount available for VEGFR-2 activation. P-Sp/OP9 coculture, VEGFR-3-deficient mouse embryos, soluble receptor competitor assays Blood High 11090062
2001 VEGFR-3 promoter contains TATA-less proximal sequences with endothelial cell-specific transcriptional activity in transfection assays; a 1.6 kb promoter fragment directed weak lymphatic endothelial expression of LacZ in transgenic mice. Reporter gene transfection, transgenic mouse analysis FASEB journal Medium 11292664
2002 VEGF-C/VEGFR-3 signaling negatively modulates VEGFR-2 activity in endothelial cells: an antagonistic VEGFR-3 antibody (AFL4) induced VEGF-A-dependent EC dispersion similar to VEGFR-2 activation, suggesting VEGFR-3 suppresses VEGFR-2 signaling to maintain vascular integrity. ES cell-derived endothelial culture, antagonistic monoclonal antibody treatment, cytological analysis Blood Medium 12393458
2003 VEGFR-3 is expressed on corneal dendritic cells (CD11c+CD45+CD11b+, MHC class II-negative immature DCs of monocytic lineage), which also upregulate VEGF-C during inflammation; this represents expression of VEGFR-3 outside the endothelial compartment. Immunofluorescence, flow cytometry, phenotypic characterization of corneal cells The American journal of pathology Medium 12819011
2009 In zebrafish, a loss-of-function mutation in the kinase insert region of flt4 impairs lymphatic vascular development. Dll4 suppresses arterial responsiveness to Vegfc/Flt4 signaling: loss of dll4 causes arterial hyperbranching driven by Vegfc/Flt4, and overexpression of dll4 inhibits Vegfc/Flt4-dependent angiogenesis. Forward genetic screen, zebrafish mutant characterization, morpholino knockdown, genetic epistasis Development High 19906867
2009 Sumoylation of the transcription factor Prox1 at Lys556 is required for Prox1 to bind DNA, activate transcription, and induce VEGFR3 expression in endothelial cells. Mutation K556R or SENP2-mediated desumoylation abolishes Prox1-induced VEGFR3 expression and lymphatic phenotypes. In vitro sumoylation assay, site-directed mutagenesis, reporter gene assay, ectopic expression in endothelial cells Journal of cell science High 19706680
2009 A homozygous VEGFR3 mutation (A855T, in the ATP-binding domain) causes recessive primary congenital lymphedema; the mutant receptor shows impaired ligand-induced internalization, reduced ERK1/2 activity, and reduced phosphorylation compared to wild-type, though not as severely as kinase-dead mutations. Patient genetic analysis, receptor function assays (internalization, phosphorylation, ERK activation) Journal of medical genetics Medium 19289394
2010 VEGFR-3 ligand-binding domain and kinase activity are required for lymphangiogenesis but not for angiogenesis. Both wild-type and kinase-dead VEGFR-3 can form heterodimers with VEGFR-2 and decrease phospho-VEGFR-2 and phospho-ERK1/2 levels in endothelial cells treated with VEGF-A. Conditional knock-in mice (ligand-binding domain deletion and kinase-dead point mutation), co-immunoprecipitation for heterodimer detection, phosphorylation assays Cell research High 20697430
2010 Tbx1 transcription factor activates Vegfr3 transcription by binding to an enhancer element in the Vegfr3 gene in endothelial cells; conditional deletion of Tbx1 in ECs causes widespread lymphangiogenesis defects. ChIP, reporter assay, conditional knockout mouse, in vitro transcription assays The Journal of cell biology High 20439995
2011 R-spondin1 (Rspo1)/Wnt signaling promotes angiogenesis in zebrafish through the Vegfc/Vegfr3(Flt4) axis: Vegfc expression is dependent on Rspo1 and Wnt, and Vegfc/Vegfr3 are necessary downstream of Rspo1-Wnt for angiogenesis. Forward genetic screen in zebrafish, morpholino knockdown, epistasis analysis, endothelial-autonomous Wnt inhibition Development High 22007135
2012 Notch signaling strongly suppresses VEGFR3 expression; loss of Notch leads to VEGFR3 upregulation and excessive sprouting. VEGFR3 kinase-activity inhibitors (but not ligand-blocking antibodies) suppress sprouting in low-Notch endothelium, indicating VEGFR3 can signal in a ligand-independent manner when Notch is inhibited. Inducible loss-of-function genetics in vivo, pharmacological inhibitors, antibody blocking in retinal vasculature Nature High 22426001
2012 miR-1236 (a mirtron) binds the 3' UTR of VEGFR3 mRNA, causing translational inhibition and specifically reducing VEGFR3 (but not VEGFR2) expression in human lymphatic endothelial cells; overexpression decreases VEGFR3 signaling, LEC migration, tube formation, and in vivo lymphangiogenesis. 3' UTR luciferase reporter assay, miRNA overexpression in LECs, in vivo lymphangiogenesis assay Arteriosclerosis, thrombosis, and vascular biology Medium 22223733
2014 VEGF-C activates AKT signaling via formation of a VEGFR3/VEGFR2 heterodimer complex (requiring neuropilin-1), while ERK1/2 is activated via VEGFR3 homodimers. Silencing VEGFR2 or neuropilin-1 abolishes VEGF-C-induced AKT but not ERK activation. Vascular endothelial phosphotyrosine phosphatase (VE-PTP) restrains both ERK and AKT pathways downstream of VEGFR3. Co-immunoprecipitation, siRNA silencing, phosphorylation assays in primary human lymphatic endothelial cells Arteriosclerosis, thrombosis, and vascular biology High 25524775
2014 Integrin-linked kinase (ILK) impedes interaction between VEGFR3 and β1 integrin; mechanical stimulation disrupts ILK-β1 integrin assembly, releasing β1 integrin to interact with VEGFR3 and hyper-activate VEGFR3 signaling. Endothelial-specific ILK deletion leads to excessive VEGFR3 phosphorylation and lymphatic overgrowth rescued by Itgb1 haploinsufficiency. Endothelial-specific conditional knockout mice, co-immunoprecipitation, phosphorylation assays, genetic rescue experiments The EMBO journal High 30518533
2015 VEGFR2 is required for postnatal retinal angiogenesis independently of VEGFR3 and Notch; VEGFR2 is required for DLL4 upregulation and for VEGFR3 functions in angiogenesis. In contrast, VEGFR3 (but not VEGFR2) is essential for postnatal lymphangiogenesis and adult lymphatic vessel maintenance. Conditional deletion of Vegfr2 and Vegfr3 in mice, Notch pathway inhibitor treatment, retinal vascular phenotyping Proceedings of the National Academy of Sciences High 25561555
2016 VEGFR3 is expressed on tumor-associated macrophages (TAMs) that infiltrate chemotherapy-treated tumors; VEGFR3-expressing macrophages induce lymphangiogenesis in a VEGF-C/VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 inhibits pro-metastatic macrophage activity. VEGFR3 blocking in murine tumor models, macrophage transfer experiments, in vivo lymphangiogenesis assay Cell reports Medium 27783948
2017 VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity: deletion of Vegfr3 in blood vascular endothelial cells upregulates VEGFR2 protein and phosphorylation, reduces VE-cadherin at cell junctions, and exacerbates vascular permeability. Concurrent Vegfr2 deletion prevents the excessive permeability seen in Vegfr3-deleted mice. Conditional Vegfr3 deletion in mice, VEGFR3 siRNA in cultured ECs, VEGFR2 phosphorylation assay, VE-cadherin localization, genetic rescue (Vegfr2 co-deletion) Circulation research High 28298294
2018 In diabetes, ROS-induced c-Src-dependent (but VEGF-C-independent) VEGFR3 phosphorylation upregulates AP-1, which increases epsin expression; elevated epsins bind and promote degradation of newly synthesized VEGFR3 in the Golgi, reducing cell-surface VEGFR3 availability and impairing lymphangiogenesis. Lymphatic-specific epsin double KO mice, endocytosis assays, VEGFR3 phosphorylation and degradation assays, corneal micropocket and Matrigel assays The Journal of clinical investigation High 30102256
2018 Heterogeneous deletion of Vegfr3 in lymphatic endothelial cells causes VEGFR3- cells to non-cell-autonomously drive lymphatic hyperplasia by inducing proliferation of neighboring VEGFR3+ LECs through contact-dependent reduction of Notch signaling. Inducible mosaic Vegfr3 deletion in mice, Notch signaling readouts, clonal analysis Nature communications High 29615616
2018 CLEC14A forms a complex with VEGFR-3 in endothelial cells; loss of CLEC14A reduces VEGFR-3 expression with concomitant increases in VEGFR-2 expression and downstream signaling, demonstrating CLEC14A as a regulator of VEGFR-2/VEGFR-3 balance. Co-immunoprecipitation, CLEC14A knockout mice, receptor expression and signaling assays The Journal of clinical investigation Medium 27991863
2018 uPARAP endocytic receptor forms a complex with both VEGFR-2 and VEGFR-3, restricts their heterodimerization, and promotes VEGFR-3 signaling through the Crk-II/JNK/paxillin/Rac1 pathway during VEGF-C-driven lymphangiogenesis. Loss of uPARAP leads to hyperbranched lymphatic vasculature in pathological conditions. Co-immunoprecipitation, uPARAP genetic knockout, VEGFR heterodimer assays, pathway inhibition, in vivo lymphangiogenesis models Nature communications High 30518756
2018 VEGFR-3 tyrosine kinase inactivation (Chy mouse with I1053F mutation) leads to retention of triglycerides in enterocytes, decreased postprandial plasma TGs, and reduced nitric oxide levels after fat bolus, demonstrating a role for VEGFR-3 signaling in chylomicron entry into intestinal lacteals. Chy mouse model (kinase-dead VEGFR3), lipid absorption assays, NO measurement, enterocyte histology Frontiers in physiology Medium 30618798
2020 In zebrafish cardiac valve development, Vegfr3/Flt4 is restricted to abluminal endocardial cells by blood flow-activated Notch and Klf2a signaling pathways. Loss of Vegfr3 disrupts valve morphogenesis and causes Notch activation in abluminal cells, revealing antagonistic roles of Vegfr3 (abluminal) and Notch (luminal) in shaping valve leaflets. Zebrafish genetic mutants and transgenic lines, mechanosensitive pathway analysis, live imaging Cell reports Medium 32668254
2021 FLT4/VEGFR3 recruits AMP-activated protein kinase (AMPK) and directly phosphorylates AMPK-α subunit at Y247 and Y441/Y442 upon bacterial infection in macrophages, thereby coordinating glycolytic reprogramming, autophagy (MAP1LC3 activation), and suppression of CASP1-dependent inflammasome activation/pyroptosis for bacterial elimination. FLT4 mutant (extracellular domain deletion) macrophages, AMPK phosphorylation assays, metabolomics, autophagy assays, AICAR rescue experiments Autophagy Medium 34632918
2021 VEGFC/VEGFR3/ERK signaling directly induces cell-cycle arrest (G1) in venous and lymphatic endothelial precursors in zebrafish, promoting expression of p53 and CDK inhibitors p27/p21, and this G1 arrest is required for vascular sprouting and differentiation. Transgenic zebrafish (cell cycle reporters), VEGFC/VEGFR3 manipulation, CDK inhibitor overexpression, live confocal imaging Cell reports Medium 34133928
2021 Mitochondrial complex III activity in lymphatic endothelial cells is required for maintaining H3K4me3 and H3K27ac at the Vegfr3 (and Prox1) genomic loci; loss of complex III causes specific downregulation of Vegfr3 and loss of LEC fate. Conditional deletion of mitochondrial complex III QPC subunit in LECs, ChIP for histone marks, gene expression analysis Science advances Medium 33931446
2022 Ang2 secreted from lymphatic endothelial cells upon VEGF-C stimulation activates Tie2 and Tie1 receptors to fully activate Akt downstream of PI3K, which is required for cell-surface presentation of VEGFR3 on LECs. Blockade of Ang2 or deletion of Tie receptors reduces VEGFR3 surface levels and inhibits lymphangiogenesis. Gene deletion of Tie1, Tie2, Ang2, PI3K-p110α in LECs; Ang2-blocking antibody; VEGFR3 surface expression assays; adult lymphangiogenesis models The Journal of clinical investigation High 35763346
2023 VEGFR3 is required for button junction formation in lymphatic capillaries; loss of Flt4 in lymphatic-specific knockout mice prevents button junction development and impairs interstitial absorption. Mechanistically, FLT4 knockdown reduces NOTCH1 expression and activation, and overexpression of the NOTCH1 intracellular domain in Flt4 knockout vessels rescues button junction formation. Lymphatic-specific Flt4 knockout mice, junction morphology analysis, NOTCH1 overexpression rescue, absorption assays Cell reports High 37454290
2023 VEGFR-3 blockade (monoclonal antibody, soluble VEGF-C/D trap, or lymphatic endothelium-specific Vegfr3 deletion) causes regression and functional impairment of dural lymphatic vessels but has no effect on CNS autoimmunity development in mice. VEGFR3-blocking antibody, soluble decoy receptor, inducible conditional Vegfr3 deletion; EAE autoimmune neuroinflammation model Science immunology High 37058549
2023 VEGF-C secreted by virally infected neurons activates VEGFR-3 on CNS macrophages, suppressing TNF-α secretion and reducing neuron apoptosis. Vegfr3 ligand-binding domain deletion in myeloid cells or VEGFR-3 kinase inhibitor treatment exacerbates encephalitis severity and neuronal damage. VEGFR-3 ligand-binding domain knockout in myeloid cells (Vegfr3ΔLBD/ΔLBD), VEGFR-3 kinase inhibitor, co-culture assays with conditioned medium, JEV infection mouse model Cell reports Medium 37167063

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 991 9435229
2008 Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 658 18594512
1999 VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. The American journal of pathology 478 10329591
2012 Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 304 22426001
2002 VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood 293 12393704
2011 Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. Genes, chromosomes & cancer 257 20949568
1992 FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer research 247 1327515
2006 The role of the VEGF-C/VEGFR-3 axis in cancer progression. British journal of cancer 222 17164762
1993 The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. The Journal of experimental medicine 220 8245783
2009 Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development (Cambridge, England) 197 19906867
2016 Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases With Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations. The American journal of surgical pathology 165 26735859
2014 TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling. Nature communications 158 25229256
1993 The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor. Oncogene 149 8386825
2001 VEGFR-3 in adult angiogenesis. The Journal of pathology 133 11745682
1994 Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene 130 7970715
2017 VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling. Circulation research 123 28298294
2005 Milroy disease and the VEGFR-3 mutation phenotype. Journal of medical genetics 121 15689446
2007 Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 119 17210781
2000 VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood 117 11090062
2010 VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell research 116 20697430
2003 Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. The American journal of pathology 116 12819011
2014 Molecular controls of lymphatic VEGFR3 signaling. Arteriosclerosis, thrombosis, and vascular biology 114 25524775
1992 FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. Cancer research 109 1310071
2015 VEGFR3 does not sustain retinal angiogenesis without VEGFR2. Proceedings of the National Academy of Sciences of the United States of America 103 25561555
2016 Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3. Cell reports 101 27783948
2021 Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer. Clinical and translational medicine 95 34323412
2011 Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3. Development (Cambridge, England) 92 22007135
1997 Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. Leukemia 84 9264375
1993 Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts. Oncogene 81 7692369
2022 Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. The Journal of clinical investigation 80 35763346
2012 SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities. Molecular cancer therapeutics 76 22584122
2019 Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer. Cancer research 73 31239267
1992 Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics 70 1319394
2021 VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis. Clinical and translational medicine 67 33783987
2006 Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas. The Journal of pathology 67 16523449
2010 Tbx1 regulates Vegfr3 and is required for lymphatic vessel development. The Journal of cell biology 65 20439995
2021 FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination. Autophagy 62 34632918
2012 FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Human mutation 61 23074044
2001 VEGFR3 gene structure, regulatory region, and sequence polymorphisms. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 61 11292664
2018 Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nature communications 55 29615616
2018 Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. The Journal of clinical investigation 54 30102256
2009 Recessive primary congenital lymphoedema caused by a VEGFR3 mutation. Journal of medical genetics 53 19289394
2012 Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis. Arteriosclerosis, thrombosis, and vascular biology 50 22223733
2008 Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines. International journal of oncology 49 18292935
2016 Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system. Angiogenesis 48 26993803
2016 Pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis in tumor lymphangiogenesis and lymphatic metastasis. Clinica chimica acta; international journal of clinical chemistry 48 27527412
2009 Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells. Journal of cell science 48 19706680
2004 Expression and significance of VEGF-C and FLT-4 in gastric cancer. World journal of gastroenterology 48 14760756
2022 VEGF-C/VEGFR-3 signalling in macrophages ameliorates acute lung injury. The European respiratory journal 47 34446463
2006 Expression of VEGFR3 in glioma endothelium correlates with tumor grade. Journal of neuro-oncology 46 17115285
2007 Elevated expression of VEGFR-3 in lymphatic endothelial cells from lymphangiomas. BMC cancer 45 17584927
2002 Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3. Blood 45 12393458
2023 Blockade of VEGFR3 signaling leads to functional impairment of dural lymphatic vessels without affecting autoimmune neuroinflammation. Science immunology 44 37058549
2021 The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases. Cardiovascular research 44 33067626
2018 Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth. The EMBO journal 44 30518533
2001 Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast. Histology and histopathology 44 11332691
2015 Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis. Oncotarget 43 25605009
2016 MicroRNA-126a Directs Lymphangiogenesis Through Interacting With Chemokine and Flt4 Signaling in Zebrafish. Arteriosclerosis, thrombosis, and vascular biology 42 27789478
2015 VEGF-C-VEGFR3/Flt4 axis regulates mammary tumor growth and metastasis in an autocrine manner. American journal of cancer research 42 25973301
1995 Biochemical characterization of two isoforms of FLT4, a VEGF receptor-related tyrosine kinase. Oncogene 42 7898938
2023 Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease. Cells 41 38201272
2018 VEGFC/VEGFR3 Signaling Regulates Mouse Spermatogonial Cell Proliferation via the Activation of AKT/MAPK and Cyclin D1 Pathway and Mediates the Apoptosis by affecting Caspase 3/9 and Bcl-2. Cell cycle (Georgetown, Tex.) 41 29169284
2014 Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma. Cytokine 41 24845798
2021 VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells. Cell reports 40 34133928
2000 VEGFc and VEGFR3 expression in human thyroid pathologies. International journal of cancer 40 10728593
2017 Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling. Oncotarget 39 27901498
2021 Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance. Science advances 38 33931446
2015 The utility of MYC and FLT4 in the diagnosis and treatment of postradiation atypical vascular lesion and angiosarcoma of the breast. Human pathology 35 25864386
2011 Lymphatic microvessel density, VEGF-C, and VEGFR-3 expression in different molecular types of breast cancer. Anticancer research 35 21617236
2007 A novel VEGFR3 mutation causes Milroy disease. American journal of medical genetics. Part A 35 17458866
1997 Characterization of murine Flt4 ligand/VEGF-C. Oncogene 35 9247316
2017 Targeting VEGFR-3/-2 signaling pathways with AD0157: a potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases. Journal of hematology & oncology 34 28629427
2021 Discovery, Synthesis, and Evaluation of Highly Selective Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Inhibitor for the Potential Treatment of Metastatic Triple-Negative Breast Cancer. Journal of medicinal chemistry 32 34351741
2013 The VEGF-C/VEGFR3 signaling pathway contributes to resolving chronic skin inflammation by activating lymphatic vessel function. Journal of dermatological science 32 24252749
2012 DNA methylation regulates expression of VEGF-R2 (KDR) and VEGF-R3 (FLT4). BMC cancer 32 22251800
2011 Suppression of vascular endothelial growth factor receptor 3 (VEGFR3) and vascular endothelial growth factor C (VEGFC) inhibits hypoxia-induced lymph node metastases in cervix cancer. Gynecologic oncology 32 21839498
2022 ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome. Stem cell research & therapy 31 36064450
2014 Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway. Cell communication and signaling : CCS 31 24708522
2014 Roles of serum and biliary CEA, CA19-9, VEGFR3, and TAC in differentiating between malignant and benign biliary obstructions. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 31 25003676
2016 Carbohydrate-binding protein CLEC14A regulates VEGFR-2- and VEGFR-3-dependent signals during angiogenesis and lymphangiogenesis. The Journal of clinical investigation 30 27991863
2015 VEGF-C/VEGFR-3 pathway promotes myocyte hypertrophy and survival in the infarcted myocardium. American journal of translational research 29 26064438
2018 VEGFR-3 Signaling Regulates Triglyceride Retention and Absorption in the Intestine. Frontiers in physiology 28 30618798
2017 Distinct transcriptional responses of lymphatic endothelial cells to VEGFR-3 and VEGFR-2 stimulation. Scientific data 28 28850122
2016 Regulation of lymphangiogenesis in the diaphragm by macrophages and VEGFR-3 signaling. Angiogenesis 27 27464987
2018 Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib. Cancer research 26 30385613
2020 Antagonistic Activities of Vegfr3/Flt4 and Notch1b Fine-tune Mechanosensitive Signaling during Zebrafish Cardiac Valvulogenesis. Cell reports 25 32668254
2014 Restoration of natural killer cell cytotoxicity by VEGFR-3 inhibition in myelogenous leukemia. Cancer letters 25 25157650
2014 Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects. Oncotarget 23 25003617
2007 Expression of VEGF-C, VEGF-D and their receptor VEGFR-3 in diffuse large B-cell lymphomas. Leukemia & lymphoma 23 17926187
2023 VEGFR3 is required for button junction formation in lymphatic vessels. Cell reports 22 37454290
2021 Qingjie Fuzheng Granule suppresses lymphangiogenesis in colorectal cancer via the VEGF-C/VEGFR-3 dependent PI3K/AKT pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 33578235
2021 Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics without Renal Dysfunction. Journal of the American Society of Nephrology : JASN 22 34551997
2018 uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis. Nature communications 22 30518756
2013 VEGFR-3 neutralization inhibits ovarian lymphangiogenesis, follicle maturation, and murine pregnancy. The American journal of pathology 22 24036251
1997 Signal transduction in human hematopoietic cells by vascular endothelial growth factor related protein, a novel ligand for the FLT4 receptor. Blood 22 9345034
2013 A VEGFR-3 antagonist increases IFN-γ expression on low functioning NK cells in acute myeloid leukemia. Journal of clinical immunology 21 23404187
2021 Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy. ACS applied materials & interfaces 20 34232612
2013 Inhibition of FAK and VEGFR-3 binding decreases tumorigenicity in neuroblastoma. Molecular carcinogenesis 20 23868727
2009 Inhibiton of RET and JAK2 signals and upregulation of VEGFR3 phosphorylation in vitro by galectin-1 in trophoblast tumor cells BeWo. Placenta 19 19900702
2023 VEGFR-3 signaling restrains the neuron-macrophage crosstalk during neurotropic viral infection. Cell reports 18 37167063

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