Affinage

Showing FLT1 — VEGFR1 is a alias.

FLT1

Vascular endothelial growth factor receptor 1 · UniProt P17948

Length
1338 aa
Mass
150.8 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLT1 (VEGFR1) is a high-affinity receptor tyrosine kinase for VEGF-A and PlGF that functions principally as a negative regulator of angiogenesis during vascular development by sequestering VEGF away from the more strongly signaling VEGFR2 (PMID:7596436, PMID:9689083, PMID:8822205). Ligand binding is mediated by the N-terminal first-to-third immunoglobulin-like domains of the ectodomain, while the fourth-to-seventh Ig region drives dimerization and kinase activation, and a fragment carrying only the first three Ig domains is sufficient to trap VEGF and block endothelial proliferation (PMID:9369935). Genetic dissection established that the FLT1 ectodomain alone supports normal embryonic vascular patterning, whereas the tyrosine kinase domain is dispensable for development but required for VEGF-driven macrophage migration (PMID:9689083). A soluble isoform (sFlt-1), generated by intronic polyadenylation within intron 13, acts as the physiologically critical VEGF decoy: it sets up local discontinuities in VEGF-A availability that pattern vessel sprouting and branching, and sFlt-1—but not membrane-bound Flt-1—rescues branching defects in flt-1-null vessels (PMID:14982871, PMID:17615362, PMID:18504303). The receptor positively regulates angiogenesis under pathological conditions when Flt-1-specific ligands such as PlGF are abundant, signaling through PI3K/Akt-Rac1 (with the adaptor RACK1) and PLCγ to drive myeloid cell migration, and through the pseudokinase co-receptor PTK7 and Neuropilin-1 co-receptor interactions to control endothelial migration and anastomosis (PMID:11221852, PMID:21212275, PMID:21460247, PMID:29263797, PMID:10842181, PMID:28246215). FLT1 also controls vascular sprouting non-cell-autonomously through expression in pericytes (PMID:29146905), and amplifies pathological angiogenesis in tumors, psoriatic keratinocytes, and arthritic synovium (PMID:18794121, PMID:31934626, PMID:38261818). Ectodomain shedding of membrane Flt-1 is executed by ADAM10/ADAM17, enhanced by PKC and limited by VEGFR2 heterodimerization and c-CBL-mediated ubiquitination (PMID:25387128); sFlt-1 additionally acts as an autocrine antagonist of VEGFR2 that sensitizes endothelial cells to inflammatory stimuli (PMID:21752276, PMID:21139021).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 High

    Established that FLT1 is essential not for endothelial differentiation but for organizing endothelial cells into functional vessels, defining its developmental role at the morphogenesis level.

    Evidence flt-1 null mouse gene targeting with in vivo developmental analysis

    PMID:7596436

    Open questions at the time
    • Did not resolve whether the defect reflects loss of signaling or loss of VEGF sequestration
    • Molecular mechanism of disorganized vascular assembly unspecified
  2. 1996 High

    Defined FLT1 ligand specificity by showing PlGF is a high-affinity FLT1-specific ligand that activates autophosphorylation and competes with VEGF, distinguishing FLT1 from VEGFR2.

    Evidence Radioligand binding and receptor autophosphorylation assays in receptor-expressing NIH3T3 cells

    PMID:8822205

    Open questions at the time
    • Downstream signaling consequences of PlGF binding not addressed
    • Did not establish in vivo ligand selectivity
  3. 1997 High

    Mapped the receptor's functional domains, separating VEGF binding (Ig1-3) from dimerization/kinase activation (Ig4-7) and demonstrating a soluble three-domain fragment can act as a VEGF trap.

    Evidence Deletion-mutant baculovirus/COS expression with binding and endothelial proliferation assays

    PMID:9369935

    Open questions at the time
    • Did not test the natural soluble isoform in vivo
    • Structural basis of high affinity not resolved
  4. 1997 Medium

    Extended FLT1 function beyond endothelium by showing functional VEGF-responsive receptors on mesangial and uterine smooth muscle cells.

    Evidence Expression, phosphorylation, and proliferation assays in primary non-endothelial cells

    PMID:7726838 PMID:9042161

    Open questions at the time
    • Physiological role of FLT1 in these cell types in vivo not established
    • Downstream pathway not defined
  5. 1998 High

    Resolved the kinase-versus-decoy question genetically: the ectodomain alone suffices for vascular development while the kinase domain is required specifically for macrophage migration.

    Evidence Flt-1 kinase-domain deletion (TK-/-) mice with developmental and macrophage migration readouts

    PMID:9689083

    Open questions at the time
    • Did not identify downstream effectors of kinase signaling
    • Did not address pathological angiogenesis context
  6. 1998 Medium

    Demonstrated the FLT1 kinase has intrinsic transforming and morphogenic potential when constitutively activated, and identified Sck/Shc as a kinase-dependent adaptor.

    Evidence Constitutively active chimera transformation assays; yeast two-hybrid with mutagenesis

    PMID:9632135 PMID:9790910

    Open questions at the time
    • Sck interaction not validated in endothelial cells
    • Relevance of forced activation to native signaling unclear
  7. 2000 High

    Identified ectodomain co-receptor interactions (Neuropilin-1) and receptor-specific signaling roles (Flt-1 homodimer in actin reorganization/migration) that explain how FLT1 modulates angiogenesis.

    Evidence SPR binding with purified proteins; receptor-specific blocking antibodies in HUVECs

    PMID:10842181 PMID:10865839

    Open questions at the time
    • Functional consequence of FLT1-NP1 competition not tested in vivo
    • Homodimer signaling readouts partly correlative
  8. 2001 Medium

    Established context-dependent positive signaling: under high PlGF-2, FLT1 kinase activity promotes tumor angiogenesis, and FLT1 controls endothelial survival via regulated ubiquitination/nuclear accumulation.

    Evidence TK-/- mice with PlGF-2 tumor models; tissue arrays, fractionation, siRNA, ubiquitination assays

    PMID:11221852 PMID:19834490

    Open questions at the time
    • Nuclear localization function mechanistically unresolved
    • Survival pathway details incomplete
  9. 2002 Medium

    Demonstrated autocrine VEGF/Flt1 signaling supports hematopoietic (megakaryocyte) maturation, broadening FLT1's roles beyond vessel patterning.

    Evidence CD34+ differentiation assays with soluble Flt-1 blockade and exogenous ligand

    PMID:12406876

    Open questions at the time
    • Receptor-proximal signaling in megakaryocytes not defined
    • In vivo requirement not tested
  10. 2004 High

    Defined the molecular determinants of PlGF-FLT1 engagement and clarified that the soluble isoform positively regulates sprouting by spatially limiting VEGF-A.

    Evidence PlGF site-directed mutagenesis with functional assays; flt-1-/- vascular cultures with sflt-1 transgene rescue

    PMID:14982871 PMID:15272021

    Open questions at the time
    • Quantitative spatial model of ligand gradients not yet formalized
    • Full-length isoform's distinct contribution unresolved here
  11. 2007 High

    Elucidated the molecular origin and regulation of sFlt-1 (intron 13 intronic polyadenylation) and external control of its release (HO-1/CO, VEGFR2-dependent), and linked FLT1 to cardioprotective signaling.

    Evidence RACE/RPA/reporter mutagenesis; HO-1 KO/CORM-2 with selective ligands; Flt-1+/- ischemic heart studies

    PMID:17389265 PMID:17448895 PMID:17615362

    Open questions at the time
    • Tissue-specific regulation of intronic polyadenylation not mapped
    • Cardiac signaling readouts largely correlative
  12. 2008 High

    Refined the spatial model, showing sFlt-1 amplifies VEGF/Flk-1 phosphorylation heterogeneity to pattern branching, and established that myeloid FLT1 amplifies tumor angiogenesis via CXCL12.

    Evidence Isoform-specific transgene rescue with Flk-1 phosphorylation mapping; TK-/- bone marrow chimeras in glioma

    PMID:18504303 PMID:18794121

    Open questions at the time
    • Mechanism setting differential mFlt-1 vs sFlt-1 expression unresolved
    • CXCL12 induction pathway downstream of FLT1 incomplete
  13. 2008 High

    Showed FLT1 transcriptional regulation (NFAT/β1-integrin/TEM8/VEGFR2) controls VEGFR2 activity, with low FLT1 driving constitutive VEGFR2 signaling in hemangioma.

    Evidence Expression profiling, NFAT reporters, blocking antibodies, soluble VEGFR1 rescue, mutational analysis

    PMID:18931684

    Open questions at the time
    • Generalizability of the NFAT/TEM8 axis to normal endothelium unclear
  14. 2009 Medium

    Identified downstream trafficking and pericyte-related effects, with VEGFR1 driving Rab4A-dependent αvβ3 integrin recycling for tubule branching and ablating pericytes to increase vascular leakage.

    Evidence Rab4A siRNA with integrin trafficking/fibronectin assays; VEGFR1-specific antibody (MF1) in vivo pericyte quantification

    PMID:19302266 PMID:20080765

    Open questions at the time
    • Receptor-proximal link to Rab4A unspecified
    • Pericyte ablation mechanism not molecularly defined
  15. 2010 High

    Established sFlt-1 as an autocrine antagonist of VEGFR2 that restrains endothelial migration/eNOS and sensitizes endothelium to inflammatory TNF-α.

    Evidence siRNA/overexpression and multiple receptor-blocking approaches with adhesion molecule and signaling readouts in HUVECs

    PMID:21139021 PMID:21752276

    Open questions at the time
    • In vivo relevance of autocrine sFlt-1 antagonism not directly tested
    • Quantitative thresholds for the switch unknown
  16. 2011 Medium

    Identified direct cytoplasmic and co-receptor partners (RACK1, PTK7) required for FLT1 kinase signaling and migration, and a PKCα-dependent role in vasculogenic mimicry.

    Evidence In vitro binding, SPR, siRNA with pathway analysis and migration/angiogenesis assays; PKC-isoform targeting with melanoma models

    PMID:21212275 PMID:21389833 PMID:21460247

    Open questions at the time
    • Structural basis of RACK1/PTK7 binding not determined
    • Hierarchy among PI3K/Akt-Rac1 effectors not resolved
  17. 2013 High

    Defined an upstream transcriptional control circuit (Wnt-Calcineurin) that activates myeloid Flt1 to suppress wound angiogenesis, with myeloid Flt1 deletion accelerating repair.

    Evidence Conditional Wntless/CNB1 and myeloid-specific Flt1 KO with wound angiogenesis quantification

    PMID:23303818

    Open questions at the time
    • Direct transcriptional targets linking calcineurin to Flt1 not detailed
  18. 2014 High

    Defined the protease and regulatory machinery of ectodomain shedding: ADAM10/ADAM17 cleavage controlled by PKC, VEGFR2 heterodimerization, and c-CBL ubiquitination.

    Evidence Metalloprotease inhibitors, ADAM overexpression/siRNA, deletion mutants, VEGFR2 co-expression, c-CBL knockdown in HUVEC/HEK293

    PMID:25387128

    Open questions at the time
    • Relative contribution of shedding versus intronic polyadenylation to soluble FLT1 pools in vivo unresolved
  19. 2017 High

    Consolidated FLT1's spatial control of vessel architecture through membrane Flt1 in anastomosis and pericyte Flt1 in sprouting, and confirmed a kinase-independent migration role in fetoplacental endothelium.

    Evidence Isoform-selective manipulation with live imaging; pericyte-specific conditional KO with retinal morphometry; FLT1/KDR siRNA in primary placental ECs

    PMID:28246215 PMID:29146905 PMID:29263797 PMID:30316329

    Open questions at the time
    • Mechanism of Akt/ERK-independent FLT1 migration signaling unidentified
    • How pericyte FLT1 shapes local VEGF gradients quantitatively unresolved
  20. 2020 Medium

    Extended FLT1 to inflammatory tissue disease, showing epidermal Flt1/Nrp1 drives Vegfa-mediated psoriasis via a Fosl1 transcriptional program, and a GRK2-PPARγ axis controls Flt1+ macrophage angiogenesis in arthritis.

    Evidence Epidermal conditional KO with ATAC/RNA-seq; GRK2 conditional KO with reporter and co-IP in arthritis model

    PMID:31934626 PMID:38261818

    Open questions at the time
    • Direct FLT1-proximal signaling in keratinocytes versus decoy role not separated
    • GRK2-PPARγ-Flt1 axis specificity to disease context unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptor-proximal signaling mechanism for FLT1's Akt/ERK-independent migration function and the structural basis of its kinase activation and co-receptor partnerships remain unresolved.
  • No structural model of the FLT1 kinase or its co-receptor complexes
  • Quantitative relationship between mFlt-1/sFlt-1 ratios and signaling outcomes not formalized
  • Kinase-independent migration effectors unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140313 molecular sequestering activity 4 GO:0001618 virus receptor activity 3 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ADAM10ADAM17CBLKDRNRP1PTK7RACK1SHCB

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Flt-1 (VEGFR1) is essential for the organization of embryonic vasculature but not for endothelial cell differentiation; homozygous flt-1 null mouse embryos formed endothelial cells but assembled them into abnormal vascular channels and died in utero, indicating Flt-1 signaling regulates endothelial cell-cell or cell-matrix interactions during vascular development. Gene targeting (flt-1 null mice), in vivo developmental analysis Nature High 7596436
1998 The extracellular domain of Flt-1 (without the tyrosine kinase domain) is sufficient for normal embryonic vascular development and angiogenesis, acting as a VEGF-trapping molecule; however, the Flt-1 tyrosine kinase domain is required for VEGF-induced macrophage migration. Targeted deletion of Flt-1 kinase domain (flt-1 TK-/- mice), in vivo developmental analysis, macrophage migration assays Proceedings of the National Academy of Sciences of the United States of America High 9689083
1996 Flt-1 (VEGFR1), but not KDR/Flk-1 (VEGFR2), is a high-affinity receptor for placenta growth factor (PlGF); PlGF competes with VEGF for Flt-1 binding, activates Flt-1 autophosphorylation, and does not signal through KDR. Radioligand binding assay (125I-VEGF competition and 125I-PlGF direct binding), receptor autophosphorylation assay, receptor-expressing NIH3T3 cells Cell growth & differentiation High 8822205
1997 Flt-1 is expressed in renal mesangial cells (not just endothelial cells) and its expression is upregulated by PDGF stimulation, concomitant with VEGF upregulation, suggesting autocrine VEGF/Flt-1 signaling in mesangial cell proliferation. RT-PCR, Northern analysis, immunoprecipitation; cultured glomerular mesangial cells Biochemical and biophysical research communications Medium 7726838
1997 Flt-1 is expressed by uterine smooth muscle cells (not just endothelial cells), and these cells phosphorylate Flt-1 and proliferate in response to VEGF stimulation, demonstrating functional VEGF receptors on non-endothelial normal cells. Northern analysis, in situ hybridization, Western analysis, receptor phosphorylation assay, cell proliferation assay in isolated and cultured uterine smooth muscle cells Laboratory investigation High 9042161
1997 The VEGF-binding domain of Flt-1 resides in the N-terminal 1st–3rd immunoglobulin-like domains; the 4th–7th Ig region is required for receptor dimerization and tyrosine kinase activation; a soluble Flt-1 fragment carrying only the first 3 Ig domains can block VEGF-dependent endothelial proliferation. Baculovirus expression of deletion mutants, ligand binding assays, COS cell expression of kinase mutants, endothelial cell proliferation inhibition assay Japanese journal of cancer research : Gann High 9369935
1998 Constitutively active forms of the Flt-1 kinase domain (BCR-FLTm chimeras with activating mutations) can transform fibroblasts, abrogate cytokine dependence in Ba/F3 cells, and induce neurite-like and tube-like structures, demonstrating that the Flt-1 kinase has transforming and morphogenic potential when activated. Retroviral mutagenesis to generate constitutively active Flt-1, cell transformation assays, cytokine-independence assay, morphology in basement membrane matrix Oncogene Medium 9632135
1998 The Shc homologue Sck binds to both Flt-1 and KDR via its SH2 domain in a kinase activity-dependent manner; mutation of Flt-1 binding sites abrogates Sck interaction, identifying Sck as a downstream signaling adaptor. Yeast two-hybrid screen, site-directed mutagenesis, domain-deletion binding studies Biochemical and biophysical research communications Medium 9790910
2000 Neuropilin-1 (NP-1) binds with high affinity (Kd ~1.8 nM) to domains 3 and 4 of Flt-1 extracellular domain, and this interaction inhibits NP-1 binding to VEGF165; Flt-1 may thus function as a negative regulator of angiogenesis by competing with VEGFR2 for NP-1 co-receptor function. BIAcore surface plasmon resonance, in vitro binding experiments with purified proteins The Journal of biological chemistry High 10842181
2000 Flt-1 homodimer signaling is required for actin reorganization during VEGF-induced HUVEC migration, whereas KDR/Flt-1 heterodimer and KDR homodimer mediate Ets-1 and MMP-1 expression and DNA synthesis; Flt-1 homodimer also contributes to focal adhesion kinase (FAK) and paxillin phosphorylation. Blocking monoclonal antibodies against Flt-1 and KDR, actin staining, Western blot for FAK/paxillin phosphorylation, reporter gene assays in HUVECs Annals of the New York Academy of Sciences Medium 10865839
2001 Flt-1 tyrosine kinase activity functions as a positive regulator of angiogenesis under pathological conditions when Flt-1-specific ligands (PlGF-2) are highly expressed by tumors; PlGF-2-overexpressing Lewis lung carcinoma grew significantly faster and with greater vascularization in wild-type mice than in Flt-1 TK-/- mice. Flt-1 TK-/- mice, tumor implantation experiments with PlGF-2- or VEGF-overexpressing Lewis lung carcinoma cells, tumor volume and vessel density measurements Cancer research High 11221852
2001 VEGFR1 is primarily localized to the nucleus of tumor-associated endothelial cells; VEGF signals through Akt/ERK to inhibit constitutive ubiquitination and induce VEGFR1 accumulation, while VEGFR1 signaling is required for endothelial cell survival; in contrast VEGFR2 undergoes JNK/c-Jun-mediated endocytosis and nuclear translocation with downregulation. Tissue microarray, nuclear fractionation, siRNA knockdown, pathway inhibitors, ubiquitination assays in endothelial cells Cell death and differentiation Medium 19834490
2002 Autocrine VEGF/Flt1 signaling through an autocrine loop contributes to optimal megakaryocyte (Mk) maturation and polyploidization; blocking VEGF-Flt1 interaction with soluble Flt-1 significantly inhibits Mk polyploidization, while exogenous VEGF or PlGF potentiates Mk maturation. CD34+ hematopoietic progenitor cell differentiation assays, soluble Flt-1 blocking experiments, exogenous VEGF/PlGF addition, flow cytometry for polyploidization Blood Medium 12406876
2004 PlGF-1 residues Asp-72 and Glu-73 (in the β3-β4 loop), Gln-27, Pro-98, Tyr-100, and glycosylation at Asn-84 are critical for Flt-1 binding; double mutation of Asp-72/Glu-73 abolishes PlGF receptor binding, activation, and in vitro tube formation and in vivo angiogenesis. Site-directed mutagenesis of PlGF, receptor binding assays, cell surface activation assays, in vitro tube formation, in vivo chorioallantoic membrane assay The Journal of biological chemistry High 15272021
2004 Loss of flt-1 leads to decreased vascular sprout formation and migration and reduced branching in vitro and in vivo (flt-1-/- embryos have defective sprouting from the dorsal aorta); rescue with a soluble flt-1 (sflt-1) transgene (but not full-length) restores branching, indicating sflt-1 positively regulates sprouting by spatially limiting VEGF-A availability. Flt-1-/- ES cell-derived vascular cultures, time-lapse GFP imaging, in vivo dorsal aorta analysis, sflt-1 transgene rescue Blood High 14982871
2007 Intronic polyadenylation signals within intron 13 of FLT1 mediate alternative cleavage/polyadenylation to generate soluble Flt-1 (sFlt-1) mRNA transcripts; an alternatively spliced exon downstream of exon 14 creates an additional sFlt-1 variant with a polyserine C-terminal tail. RNase protection assay, Northern blot, 3' RACE, mutagenesis of polyadenylation signal sequences in reporter assay FASEB journal High 17615362
2007 HO-1/CO pathway negatively regulates sFlt-1 release from endothelial cells; VEGF-induced sFlt-1 release is VEGFR2-dependent (demonstrated using VEGF-E, PlGF, and VEGFR2-specific inhibitor SU-1498); CO-releasing molecule (CORM-2) inhibits sFlt-1 release and VEGFR2 phosphorylation. Adenoviral HO-1 overexpression, HO-1-/- mice, selective receptor ligands (VEGF-E, PlGF), VEGFR2-specific inhibitor, CORM-2 treatment, ELISA Circulation High 17389265
2007 Flt-1 signaling is required for VEGF-mediated cardiac ischemic preconditioning; Flt-1+/- knockout mouse hearts show impaired preconditioning-mediated cardioprotection, with pronounced inhibition of iNOS, p-Akt, p-eNOS, STAT3, CREB, and HO-1 compared to wild-type. Flt-1+/- knockout mice, isolated working heart ischemia/reperfusion protocol, Western blot for signaling intermediates, RT-PCR for HO-1 Free radical biology & medicine Medium 17448895
2008 Soluble Flt-1 (sFlt-1) more efficiently than membrane-tethered Flt-1 (mFlt-1) amplifies spatial heterogeneity in Flk-1 phosphorylation levels across developing vessels; only sFlt-1 rescues vessel branching defects in flt-1-/- mutant vessels, demonstrating that sFlt-1 sets up local discontinuities in VEGF-A ligand availability that are critical for proper branching. Flt-1 isoform transgene rescue in ES cell-derived flt-1-/- vessels, Flk-1 Y1173 phosphorylation analysis, reporter gene expression analysis The Journal of cell biology High 18504303
2008 Flt-1 signaling in bone marrow-derived myeloid cells (macrophages) is essential to amplify the angiogenic response and promote glioma growth; Flt-1 TK-/- bone marrow transplantation reduces tumor volume, vascularization, and myeloid cell infiltration in gliomas, with SDF-1/CXCL12 identified as a downstream mediator. Bone marrow transplantation of Flt-1 TK-/- cells into irradiated recipients, orthotopic glioma implantation, tumor volume and vessel density measurement, CXCL12 ELISA Cancer research High 18794121
2008 Low VEGFR1 (FLT1) expression in hemangioma endothelial cells causes VEGF-dependent constitutive activation of VEGFR2 and downstream signaling; FLT1 transcription in these cells is NFAT-dependent, regulated by a pathway involving β1 integrin, TEM8, and VEGFR2. Gene expression profiling, NFAT reporter assays, blocking antibodies, soluble VEGFR1 rescue experiments, mutational analysis of VEGFR2 and TEM8 Nature medicine High 18931684
2009 VEGFR1 activation by VEGF or PlGF ablates pericytes from mature retinal vasculature through VEGFR1-mediated signaling, leading to increased vascular leakage; VEGFR1 blockade (but not VEGFR2 blockade) restores pericyte coverage. Systemic VEGF/PlGF delivery by protein implantation, tumor models, adenoviral vectors; VEGFR1-specific neutralizing antibody (MF1); pericyte quantification by immunofluorescence Proceedings of the National Academy of Sciences of the United States of America Medium 20080765
2009 VEGFR1 engagement activates a Rab4A-dependent recycling pathway that transports αvβ3 integrin from early endosomes to the plasma membrane, which is required for VEGF-driven fibronectin polymerization and endothelial tubule branching. VEGFR1 activation in endothelial cells, Rab4A siRNA knockdown, αvβ3 integrin trafficking assay, fibronectin polymerization assay, organotypic angiogenesis model Traffic (Copenhagen, Denmark) Medium 19302266
2010 Soluble Flt-1 (sFlt-1) autocrine signaling controls endothelial cell function: VEGF-A induces sFlt-1 mRNA and protein via a VEGFR2/PI3K-dependent mechanism; siRNA knockdown of sFlt-1 increases eNOS activation, migration, and tube formation, while sFlt-1 overexpression suppresses VEGFR2 Tyr951 phosphorylation and ERK1/2 activation. siRNA knockdown, adenoviral overexpression, VEGFR-2 phosphorylation assays, eNOS phosphorylation, tube formation assay, cell migration assay in HUVECs Vascular cell Medium 21752276
2010 Soluble Flt-1 (sFlt-1) sensitizes endothelial cells to pro-inflammatory TNF-α by antagonizing autocrine VEGF-A/PlGF signaling through both Flt-1 and VEGFR2; blockade of either receptor pathway increases ICAM-1, VCAM-1, ET-1, vWF expression and reduces Akt and eNOS phosphorylation. Recombinant sFlt1, anti-Flt1 and anti-KDR antibodies, VEGFR TK inhibitor (SU5614), FLT1/KDR siRNA knockdown, TNF-α stimulation, adhesion molecule ELISA, leukocyte adhesion assay Cardiovascular research High 21139021
2011 RACK1 (receptor for activated protein kinase C 1) binds directly to Flt-1 in vitro and is required for VEGF/Flt-1-mediated cell migration; RACK1 knockdown suppresses VEGF-driven migration without affecting proliferation and acts through the PI3K/Akt-Rac1 signaling pathway. In vitro binding assay, siRNA knockdown of RACK1, cell migration assay, PI3K/Akt/Rac1 pathway analysis in Flt-1-expressing AG1-G1-Flt1 cells The Journal of biological chemistry Medium 21212275
2011 PTK7 (a pseudokinase) forms a receptor complex specifically with Flt-1 (but not VEGFR2 or Flt-4) verified by surface plasmon resonance; VEGF-A intensifies this interaction; PTK7 is required for Flt-1 phosphorylation and downstream Akt and FAK signaling, and for Flt-1-mediated endothelial cell migration and angiogenesis. Co-immunoprecipitation, surface plasmon resonance analysis, siRNA knockdown of PTK7, Flt-1 phosphorylation assay, Akt/FAK Western blot, in vitro angiogenesis assay, in vivo VEGF-A pellet angiogenesis model Blood High 21460247
2011 VEGFR1 knockdown in melanoma cells completely disrupts Matrigel-induced capillary-like structure (CLS) formation (vasculogenic mimicry), whereas VEGFR2 kinase inhibition does not; among PKC isoforms, PKCα (but not PKCδ) is the downstream effector of VEGFR1-mediated CLS formation. siRNA knockdown of VEGFR1, VEGFR2-specific kinase inhibitor (PTKi-II), PKC isoform siRNA/inhibitors, Matrigel tube formation assay, in vivo allograft B16/F10 melanoma Melanoma research Medium 21389833
2013 Macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound vasculature; noncanonical Wnt signaling activates Flt1 expression in myeloid cells (requiring calcineurin function), and myeloid-specific Flt1 deletion enhances wound angiogenesis and accelerates repair. Conditional deletion of Wntless/GPR177 and CNB1 in macrophages, myeloid-specific Flt1 conditional KO, wound angiogenesis quantification Blood High 23303818
2014 N-terminal ectodomain cleavage of membrane-bound Flt-1 is mediated by ADAM10 and ADAM17 metalloproteases; PKC activation increases Flt-1 abundance and cleavage; the intracellular domain of Flt-1 contains a degradation domain; VEGFR2 co-expression reduces Flt-1 cleavage by maintaining Flt-1 as a heterodimer; c-CBL ubiquitin ligase knockdown increases Flt-1 expression. Metalloprotease inhibitors, ADAM10/ADAM17 overexpression and siRNA knockdown, PKC activation, cytosolic domain deletion mutants, VEGFR2 co-expression, c-CBL knockdown in HUVEC and HEK293 cells PloS one High 25387128
2017 Flt-1 (VEGFR1) expression by pericytes spatially restricts VEGF signaling; pericyte-specific inactivation of VEGFR1 in mice causes loss of side branches and vessel enlargement, phenocopying pericyte depletion and VEGF-A injection; pericyte VEGFR1 is required for controlled endothelial sprouting in the postnatal retina. Pericyte-specific conditional Vegfr1 KO mice, pharmacological pericyte depletion, intraocular VEGF-A injection, retinal vascular morphometry Nature communications High 29146905
2017 Stable anastomotic connections between blood vessel sprouts are spatially regulated by membrane-localized Flt1 (mFlt1); endothelial cells at target sites with reduced mFlt1 (but not soluble Flt1) are more likely to form stable connections with incoming sprouts, indicating that relative mFlt1 expression—by modulating local VEGFA signaling—controls selection of stable connections. Flt1 mutant mouse endothelial cell in vivo analysis, live imaging of human endothelial cells, isoform-selective knockdown (mFlt1 vs sFlt1), sprouting and contact dynamics quantification Development (Cambridge, England) High 28246215
2017 FLT1 promotes migration of human fetoplacental endothelial cells (but not proliferation); FLT1 knockdown impairs wound scratch closure and tube formation, and these effects are Akt/ERK-independent, in contrast to KDR-mediated VEGFA signaling. RNA interference of FLT1 and KDR separately, wound scratch assay, tube formation assay, MTT proliferation assay, Western blot for Akt/ERK signaling in primary human fetoplacental ECs Placenta Medium 30316329
2017 VEGFR1 promotes macrophage migration through PLCγ and PI3K pathways, and macrophage proliferation through a PLCγ pathway; these pathway assignments are supported by both computational modeling and empirical pharmacological inhibition experiments. Computational signaling model, pharmacological pathway inhibitors (PLCγ and PI3K inhibitors), macrophage migration and proliferation assays NPJ systems biology and applications Medium 29263797
2020 Epidermal Flt1 (together with Nrp1) mediates Vegfa-driven psoriatic disease in keratinocytes; conditional deletion of Flt1 or Nrp1 in epidermal cells inhibits psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion; transcriptional/chromatin profiling identified Fosl1 as a key downstream regulator of the Vegfa/Nrp1/Flt1 network in keratinocytes. Conditional epidermal-specific KO of Flt1 and Nrp1, psoriasis mouse models, transcriptional and chromatin profiling (ATAC-seq/RNA-seq), anti-Nrp1 antibody treatment Science advances High 31934626
2021 VEGFR1 tyrosine kinase signaling promotes pulmonary fibrosis; the review synthesizes genetic and pharmacological evidence that blocking VEGFR1-TK signal is beneficial in fibrosis models. Review/synthesis of genetic and pharmacological studies (Flt-1 TK-/- models and TK inhibitor studies) Inflammation and regeneration Low 34082837
2023 GRK2 inhibits Flt-1+ macrophage-mediated angiogenesis in rheumatoid arthritis via a GRK2-PPARγ signaling axis; excess GRK2 membrane recruitment reduces PPARγ ligand-binding domain activation and thereby enhances Flt-1 transcription in macrophages, promoting migration and synovial angiogenesis. GRK2 conditional KO (GRK2f/fLyz2-Cre+/- mice), collagen-induced arthritis model, RNA-seq, dual-luciferase reporter assay, co-IP for GRK2-PPARγ interaction, GRK2 activity inhibitor treatment Acta pharmaceutica Sinica. B Medium 38261818

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 2092 7596436
1998 Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proceedings of the National Academy of Sciences of the United States of America 849 9689083
2007 Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 330 17389265
2009 VEGFR1-activity-independent metastasis formation. Nature 311 19759568
2008 Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature medicine 282 18931684
2021 VEGFR1 signaling in retinal angiogenesis and microinflammation. Progress in retinal and eye research 270 33640465
2001 Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer research 265 11221852
1996 Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 264 8822205
2000 Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen--a review. Placenta 253 10831117
1996 VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. The American journal of physiology 248 8928889
2009 Positive and negative modulation of angiogenesis by VEGFR1 ligands. Science signaling 239 19244214
2000 The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. The Journal of biological chemistry 233 10842181
1996 Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Human reproduction (Oxford, England) 232 8671397
2001 Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). The international journal of biochemistry & cell biology 220 11312109
2017 Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. Nature communications 206 29146905
1995 Colocalisation of vascular endothelial growth factor and its Flt-1 receptor in human placenta. Growth factors (Chur, Switzerland) 202 8619929
2017 Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nature genetics 176 28628106
2002 Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Annals of the New York Academy of Sciences 167 12543719
2004 The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood 166 14982871
2009 VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell death and differentiation 155 19834490
2010 miR-200 Inhibits lung adenocarcinoma cell invasion and metastasis by targeting Flt1/VEGFR1. Molecular cancer research : MCR 154 21115742
2013 Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and endoglin. PloS one 153 23437230
2008 The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. The Journal of cell biology 145 18504303
1997 Uterine smooth muscle cells express functional receptors (flt-1 and KDR) for vascular permeability factor/vascular endothelial growth factor. Laboratory investigation; a journal of technical methods and pathology 139 9042161
2008 Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer research 131 18794121
2002 Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood 127 12406876
2010 Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling. Cardiovascular research 123 21139021
2000 Properties of two VEGF receptors, Flt-1 and KDR, in signal transduction. Annals of the New York Academy of Sciences 112 10865839
2005 Vascular endothelial growth factor (VEGF) and soluble VEGF receptor FLT-1 in diabetic nephropathy. Kidney international 109 15610240
2005 Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis. Journal of controlled release : official journal of the Controlled Release Society 107 15970348
2009 VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proceedings of the National Academy of Sciences of the United States of America 98 20080765
2011 RACK1 regulates VEGF/Flt1-mediated cell migration via activation of a PI3K/Akt pathway. The Journal of biological chemistry 91 21212275
1995 Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: Flt-1 and VEGF expression in renal mesangial cells. Biochemical and biophysical research communications 84 7726838
2007 Intronic polyadenylation signal sequences and alternate splicing generate human soluble Flt1 variants and regulate the abundance of soluble Flt1 in the placenta. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 80 17615362
1999 Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. Journal of cancer research and clinical oncology 77 10541969
2011 Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye. PloS one 74 21731737
2001 Adenovirus-mediated soluble FLT-1 gene therapy for ovarian carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 73 11448924
2002 Soluble FLT-1 expression suppresses carcinomatous ascites in nude mice bearing ovarian cancer. Cancer research 70 11929819
2011 Flt-1 regulates vascular endothelial cell migration via a protein tyrosine kinase-7-dependent pathway. Blood 69 21460247
2002 Expression of vascular endothelial growth factor and its receptors KDR and Flt-1 in gastric cancer cells. World journal of gastroenterology 66 12439912
2017 VEGFR1 promotes cell migration and proliferation through PLCγ and PI3K pathways. NPJ systems biology and applications 65 29263797
2006 Vascular endothelial growth factor, FLT-1, and FLK-1 analysis in a pancreatic cancer tissue microarray. Cancer 62 16532435
2011 VEGFR1 and PKCα signaling control melanoma vasculogenic mimicry in a VEGFR2 kinase-independent manner. Melanoma research 59 21389833
2011 Involvement of Flt-1 (VEGF receptor-1) in cancer and preeclampsia. Proceedings of the Japan Academy. Series B, Physical and biological sciences 59 21558755
2005 Flt-1 intraceptors inhibit hypoxia-induced VEGF expression in vitro and corneal neovascularization in vivo. Investigative ophthalmology & visual science 59 15851564
2011 Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis. Vascular cell 58 21752276
1997 Coexpression of flt-3 ligand/flt-3 and SCF/c-kit signal transduction system in bile-duct-ligated SI and W mice. The American journal of pathology 58 9094974
2005 FLT-3: a new focus in the understanding of acute leukemia. The international journal of biochemistry & cell biology 57 15778081
2018 MicroRNA-134 inhibits osteosarcoma angiogenesis and proliferation by targeting the VEGFA/VEGFR1 pathway. The FEBS journal 55 29474747
1997 Characterization of the extracellular domain in vascular endothelial growth factor receptor-1 (Flt-1 tyrosine kinase). Japanese journal of cancer research : Gann 54 9369935
2009 Analysis of VEGF, Flt-1, Flk-1, nestin and MMP-9 in relation to astrocytoma pathogenesis and progression. Neoplasma 53 19473053
2018 VEGFR1 and VEGFR2 in Alzheimer's Disease. Journal of Alzheimer's disease : JAD 51 29226875
2013 Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair. Blood 51 23303818
2003 Distribution of Flk-1 and Flt-1 receptors in neonatal and adult rat brains. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 51 12923895
1996 Coexpression of flt-1, flt-4 and KDR in freshly isolated and cultured human endothelial cells. Biochemical and biophysical research communications 50 8630024
2011 Soluble Flt-1 and PlGF: new markers of early pregnancy loss? PloS one 49 21448460
2010 Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades. Molecular cancer therapeutics 49 20103598
2000 Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues. The Journal of urology 49 10893635
1998 Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials. Oncogene 49 9632135
2020 Epidermal autonomous VEGFA/Flt1/Nrp1 functions mediate psoriasis-like disease. Science advances 48 31934626
2006 Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo. Biomaterials 48 16814378
2004 Identification of placenta growth factor determinants for binding and activation of Flt-1 receptor. The Journal of biological chemistry 46 15272021
2003 Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils. American journal of respiratory cell and molecular biology 46 14607815
2017 Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis. Development (Cambridge, England) 45 28246215
2014 Autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associates with aggressive osteosarcoma. Molecular cancer research : MCR 45 24759089
2001 Chronic hypoxia attenuates resting and exercise-induced VEGF, flt-1, and flk-1 mRNA levels in skeletal muscle. Journal of applied physiology (Bethesda, Md. : 1985) 45 11247956
2017 FLT1 and transcriptome-wide polyadenylation site (PAS) analysis in preeclampsia. Scientific reports 44 28939845
2008 Natural selection of FLT1 alleles and their association with malaria resistance in utero. Proceedings of the National Academy of Sciences of the United States of America 44 18779584
1999 Immunolocalisation of the VEGF receptors FLT-1, KDR, and FLT-4 in diabetic retinopathy. The British journal of ophthalmology 42 10434875
2015 Applications of PET imaging with the proliferation marker [18F]-FLT. The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... 41 25737423
2013 GDNF increases cell motility in human colon cancer through VEGF-VEGFR1 interaction. Endocrine-related cancer 41 24165321
2019 Role of VEGFR-1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib. Journal of cellular and molecular medicine 40 31758648
2010 Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer. Genes & cancer 40 21779435
2000 Co-expression of vascular endothelial growth factor and its receptor flt-1 in malignant pleural mesothelioma. Respiration; international review of thoracic diseases 40 10705260
2019 VEGFR1+ Metastasis-Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome. Clinical cancer research : an official journal of the American Association for Cancer Research 39 31239322
2016 Flt-1 (VEGFR-1) coordinates discrete stages of blood vessel formation. Cardiovascular research 39 27142980
2009 VEGFR1 (Flt1) regulates Rab4 recycling to control fibronectin polymerization and endothelial vessel branching. Traffic (Copenhagen, Denmark) 39 19302266
2016 Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney. Cell and tissue research 37 26928042
2015 A VEGFR1 antagonistic peptide inhibits tumor growth and metastasis through VEGFR1-PI3K-AKT signaling pathway inhibition. American journal of cancer research 36 26693066
2015 Expression and localization of vascular endothelial growth factor A (VEGFA) and its two receptors (VEGFR1/FLT1 and VEGFR2/FLK1/KDR) in the canine corpus luteum and utero-placental compartments during pregnancy and at normal and induced parturition. General and comparative endocrinology 35 26414127
2012 Morpholino-mediated increase in soluble Flt-1 expression results in decreased ocular and tumor neovascularization. PloS one 35 22438952
2002 Soluble flt-1 and the angiopoietins in the development and regulation of placental vasculature. Journal of anatomy 35 12162728
2010 TGF-beta1 induces mouse dendritic cells to express VEGF and its receptor (Flt-1) under hypoxic conditions. Experimental & molecular medicine 33 20631490
2007 VEGFR1 (Flt-1+/-) gene knockout leads to the disruption of VEGF-mediated signaling through the nitric oxide/heme oxygenase pathway in ischemic preconditioned myocardium. Free radical biology & medicine 33 17448895
2004 Induction of VEGF and its Flt-1 receptor after sciatic nerve crush injury. Neuroreport 33 15486493
2009 Soluble Flt-1 gene transfer ameliorates neointima formation after wire injury in flt-1 tyrosine kinase-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 32 19164801
2022 Conjugation of VEGFR1/R2-targeting peptide with gold nanoparticles to enhance antiangiogenic and antitumoral activity. Journal of nanobiotechnology 31 34983556
2001 Expression of vascular endothelial growth factor and its receptors Flt-1 and KDR/Flk-1 in chronic cyclosporine nephrotoxicity. Transplantation 31 11468554
1998 Sck interacts with KDR and Flt-1 via its SH2 domain. Biochemical and biophysical research communications 31 9790910
2021 FOXK2 transcriptionally activating VEGFA induces apatinib resistance in anaplastic thyroid cancer through VEGFA/VEGFR1 pathway. Oncogene 29 34489549
2018 FMS-like tyrosine kinase 1 (FLT1) is a key regulator of fetoplacental endothelial cell migration and angiogenesis. Placenta 28 30316329
2023 GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis. Acta pharmaceutica Sinica. B 26 38261818
2021 VEGFR1-tyrosine kinase signaling in pulmonary fibrosis. Inflammation and regeneration 26 34082837
2021 HOTAIR regulates colorectal cancer stem cell properties and promotes tumorigenicity by sponging miR-211-5p and modulating FLT-1. Cell cycle (Georgetown, Tex.) 26 34470574
2007 Expression and function of vascular endothelial growth factor receptors (Flt-1 and Flk-1) in vascular adventitial fibroblasts. Journal of molecular and cellular cardiology 25 17651752
2017 Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity. Stroke 24 28325846
2019 Metabolomics Identifies Placental Dysfunction and Confirms Flt-1 (FMS-Like Tyrosine Kinase Receptor 1) Biomarker Specificity. Hypertension (Dallas, Tex. : 1979) 23 31495279
2021 PIGF and Flt-1 on the surface of macrophages induces the production of TGF-β1 by polarized tumor-associated macrophages to promote lung cancer angiogenesis. European journal of pharmacology 22 34610279
2004 Immature B cell malignancies synthesize VEGF, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). Leukemia research 22 14654077
2014 N-terminal cleavage and release of the ectodomain of Flt1 is mediated via ADAM10 and ADAM 17 and regulated by VEGFR2 and the Flt1 intracellular domain. PloS one 21 25387128

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