{"gene":"FLT1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Gene targeting (flt-1 null mice), in vivo developmental analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, replicated and widely cited foundational study","pmids":["7596436"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Targeted deletion of Flt-1 kinase domain (flt-1 TK-/- mice), in vivo developmental analysis, macrophage migration assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotypic readouts (vascular development and macrophage migration), multiple orthogonal endpoints","pmids":["9689083"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Radioligand binding assay (125I-VEGF competition and 125I-PlGF direct binding), receptor autophosphorylation assay, receptor-expressing NIH3T3 cells","journal":"Cell growth & differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding and kinase activity assays with direct ligand-receptor binding, replicated by multiple subsequent studies","pmids":["8822205"],"is_preprint":false},{"year":1997,"finding":"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.","method":"RT-PCR, Northern analysis, immunoprecipitation; cultured glomerular mesangial cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — expression in non-endothelial cells confirmed by multiple methods in single lab","pmids":["7726838"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Northern analysis, in situ hybridization, Western analysis, receptor phosphorylation assay, cell proliferation assay in isolated and cultured uterine smooth muscle cells","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-level evidence: receptor expression, phosphorylation, and proliferative response all demonstrated in same primary cell system","pmids":["9042161"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Baculovirus expression of deletion mutants, ligand binding assays, COS cell expression of kinase mutants, endothelial cell proliferation inhibition assay","journal":"Japanese journal of cancer research : Gann","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic domain deletion mutagenesis combined with binding assays and functional readout in single study","pmids":["9369935"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Retroviral mutagenesis to generate constitutively active Flt-1, cell transformation assays, cytokine-independence assay, morphology in basement membrane matrix","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-based functional assays, single lab, gain-of-function approach","pmids":["9632135"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Yeast two-hybrid screen, site-directed mutagenesis, domain-deletion binding studies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast two-hybrid with domain mutagenesis, single lab","pmids":["9790910"],"is_preprint":false},{"year":2000,"finding":"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.","method":"BIAcore surface plasmon resonance, in vitro binding experiments with purified proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro binding with quantified Kd, domain-mapping, single lab","pmids":["10842181"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Blocking monoclonal antibodies against Flt-1 and KDR, actin staining, Western blot for FAK/paxillin phosphorylation, reporter gene assays in HUVECs","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific blocking antibodies used to dissect receptor-specific signaling, multiple readouts, single lab","pmids":["10865839"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Flt-1 TK-/- mice, tumor implantation experiments with PlGF-2- or VEGF-overexpressing Lewis lung carcinoma cells, tumor volume and vessel density measurements","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with in vivo tumor angiogenesis readout, ligand specificity control included","pmids":["11221852"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Tissue microarray, nuclear fractionation, siRNA knockdown, pathway inhibitors, ubiquitination assays in endothelial cells","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, siRNA, pathway inhibitors), single lab","pmids":["19834490"],"is_preprint":false},{"year":2002,"finding":"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.","method":"CD34+ hematopoietic progenitor cell differentiation assays, soluble Flt-1 blocking experiments, exogenous VEGF/PlGF addition, flow cytometry for polyploidization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking assay combined with gain-of-function, defined cellular phenotype, single lab","pmids":["12406876"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Site-directed mutagenesis of PlGF, receptor binding assays, cell surface activation assays, in vitro tube formation, in vivo chorioallantoic membrane assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis combined with binding and functional readouts in vitro and in vivo, single lab","pmids":["15272021"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Flt-1-/- ES cell-derived vascular cultures, time-lapse GFP imaging, in vivo dorsal aorta analysis, sflt-1 transgene rescue","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined morphogenetic phenotype, in vivo validation, and rescue experiment with isoform specificity","pmids":["14982871"],"is_preprint":false},{"year":2007,"finding":"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.","method":"RNase protection assay, Northern blot, 3' RACE, mutagenesis of polyadenylation signal sequences in reporter assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods including mutagenesis-validated reporter assay, defining molecular mechanism of sFlt1 generation","pmids":["17615362"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Adenoviral HO-1 overexpression, HO-1-/- mice, selective receptor ligands (VEGF-E, PlGF), VEGFR2-specific inhibitor, CORM-2 treatment, ELISA","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches including genetic KO, pharmacological inhibition, and selective ligands in same study","pmids":["17389265"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Flt-1+/- knockout mice, isolated working heart ischemia/reperfusion protocol, Western blot for signaling intermediates, RT-PCR for HO-1","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cardiac phenotype and multiple molecular readouts, single lab","pmids":["17448895"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Flt-1 isoform transgene rescue in ES cell-derived flt-1-/- vessels, Flk-1 Y1173 phosphorylation analysis, reporter gene expression analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue with isoform-specific transgenes, multiple orthogonal readouts, mechanistic dissection of sFlt-1 vs mFlt-1 function","pmids":["18504303"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Bone marrow transplantation of Flt-1 TK-/- cells into irradiated recipients, orthotopic glioma implantation, tumor volume and vessel density measurement, CXCL12 ELISA","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — bone marrow chimera approach with cell-type-specific KO, multiple tumor models and molecular readouts","pmids":["18794121"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Gene expression profiling, NFAT reporter assays, blocking antibodies, soluble VEGFR1 rescue experiments, mutational analysis of VEGFR2 and TEM8","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, rescue experiments, antibody blockade, mutational analysis), mechanistic pathway established in primary cells","pmids":["18931684"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Systemic VEGF/PlGF delivery by protein implantation, tumor models, adenoviral vectors; VEGFR1-specific neutralizing antibody (MF1); pericyte quantification by immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo receptor-specific blockade with quantitative pericyte readout, single lab","pmids":["20080765"],"is_preprint":false},{"year":2009,"finding":"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.","method":"VEGFR1 activation in endothelial cells, Rab4A siRNA knockdown, αvβ3 integrin trafficking assay, fibronectin polymerization assay, organotypic angiogenesis model","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple mechanistic readouts, single lab","pmids":["19302266"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown, adenoviral overexpression, VEGFR-2 phosphorylation assays, eNOS phosphorylation, tube formation assay, cell migration assay in HUVECs","journal":"Vascular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both gain- and loss-of-function with multiple molecular endpoints, single lab","pmids":["21752276"],"is_preprint":false},{"year":2010,"finding":"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.","method":"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","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal blocking approaches (recombinant protein, antibodies, kinase inhibitor, siRNA) all confirm same mechanism","pmids":["21139021"],"is_preprint":false},{"year":2011,"finding":"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.","method":"In vitro binding assay, siRNA knockdown of RACK1, cell migration assay, PI3K/Akt/Rac1 pathway analysis in Flt-1-expressing AG1-G1-Flt1 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus siRNA with pathway analysis, single lab","pmids":["21212275"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — SPR-confirmed direct interaction, siRNA KD with defined molecular and cellular phenotype, in vivo validation","pmids":["21460247"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown of VEGFR1, VEGFR2-specific kinase inhibitor (PTKi-II), PKC isoform siRNA/inhibitors, Matrigel tube formation assay, in vivo allograft B16/F10 melanoma","journal":"Melanoma research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific siRNA plus isoform-specific PKC targeting, in vivo confirmation, single lab","pmids":["21389833"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Conditional deletion of Wntless/GPR177 and CNB1 in macrophages, myeloid-specific Flt1 conditional KO, wound angiogenesis quantification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO alleles with defined pathway epistasis and quantitative phenotypic readouts","pmids":["23303818"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic gain- and loss-of-function mutagenesis and knockdown experiments with multiple molecular mechanisms elucidated in single study","pmids":["25387128"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Pericyte-specific conditional Vegfr1 KO mice, pharmacological pericyte depletion, intraocular VEGF-A injection, retinal vascular morphometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with phenotypic recapitulation by orthogonal pharmacological approach","pmids":["29146905"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro complementary approaches with isoform-specific manipulation and live-imaging readouts","pmids":["28246215"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts and signaling pathway analysis, single lab in primary cells","pmids":["30316329"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Computational signaling model, pharmacological pathway inhibitors (PLCγ and PI3K inhibitors), macrophage migration and proliferation assays","journal":"NPJ systems biology and applications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — empirical validation of computational model with pathway inhibitors, single lab","pmids":["29263797"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Conditional epidermal-specific KO of Flt1 and Nrp1, psoriasis mouse models, transcriptional and chromatin profiling (ATAC-seq/RNA-seq), anti-Nrp1 antibody treatment","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models with orthogonal pharmacological confirmation, genome-scale mechanistic profiling","pmids":["31934626"],"is_preprint":false},{"year":2021,"finding":"VEGFR1 tyrosine kinase signaling promotes pulmonary fibrosis; the review synthesizes genetic and pharmacological evidence that blocking VEGFR1-TK signal is beneficial in fibrosis models.","method":"Review/synthesis of genetic and pharmacological studies (Flt-1 TK-/- models and TK inhibitor studies)","journal":"Inflammation and regeneration","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper synthesizing prior evidence without new primary mechanistic experiments","pmids":["34082837"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with reporter assay and co-IP to define GRK2-PPARγ-Flt1 axis, multiple methods, single lab","pmids":["38261818"],"is_preprint":false}],"current_model":"FLT1/VEGFR1 is a high-affinity receptor for VEGF-A, PlGF, and VEGF-B whose extracellular domain acts as a VEGF decoy (via both membrane-bound and alternatively spliced soluble forms, sFlt-1, generated by intronic polyadenylation) to negatively regulate physiological angiogenesis during embryogenesis, while its tyrosine kinase domain—though weaker than VEGFR2—mediates positive signaling for macrophage/myeloid cell migration (via PI3K/Akt-Rac1/RACK1 and PLCγ pathways), endothelial cell migration and anastomosis (modulated by mFlt-1 spatial gradient), pericyte-dependent control of sprouting, and pathological angiogenesis under conditions of excess Flt-1-specific ligands; ectodomain shedding is mediated by ADAM10/ADAM17 and regulated by VEGFR2 heterodimerization, PKC, and c-CBL-mediated ubiquitination, while sFlt-1 further acts as an autocrine regulator that sensitizes endothelial cells to inflammatory stimuli by antagonizing VEGFR2 signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1995,"claim":"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","pmids":["7596436"],"confidence":"High","gaps":["Did not resolve whether the defect reflects loss of signaling or loss of VEGF sequestration","Molecular mechanism of disorganized vascular assembly unspecified"]},{"year":1996,"claim":"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","pmids":["8822205"],"confidence":"High","gaps":["Downstream signaling consequences of PlGF binding not addressed","Did not establish in vivo ligand selectivity"]},{"year":1997,"claim":"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","pmids":["9369935"],"confidence":"High","gaps":["Did not test the natural soluble isoform in vivo","Structural basis of high affinity not resolved"]},{"year":1997,"claim":"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","pmids":["7726838","9042161"],"confidence":"Medium","gaps":["Physiological role of FLT1 in these cell types in vivo not established","Downstream pathway not defined"]},{"year":1998,"claim":"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","pmids":["9689083"],"confidence":"High","gaps":["Did not identify downstream effectors of kinase signaling","Did not address pathological angiogenesis context"]},{"year":1998,"claim":"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","pmids":["9632135","9790910"],"confidence":"Medium","gaps":["Sck interaction not validated in endothelial cells","Relevance of forced activation to native signaling unclear"]},{"year":2000,"claim":"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","pmids":["10842181","10865839"],"confidence":"High","gaps":["Functional consequence of FLT1-NP1 competition not tested in vivo","Homodimer signaling readouts partly correlative"]},{"year":2001,"claim":"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","pmids":["11221852","19834490"],"confidence":"Medium","gaps":["Nuclear localization function mechanistically unresolved","Survival pathway details incomplete"]},{"year":2002,"claim":"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","pmids":["12406876"],"confidence":"Medium","gaps":["Receptor-proximal signaling in megakaryocytes not defined","In vivo requirement not tested"]},{"year":2004,"claim":"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","pmids":["15272021","14982871"],"confidence":"High","gaps":["Quantitative spatial model of ligand gradients not yet formalized","Full-length isoform's distinct contribution unresolved here"]},{"year":2007,"claim":"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","pmids":["17615362","17389265","17448895"],"confidence":"High","gaps":["Tissue-specific regulation of intronic polyadenylation not mapped","Cardiac signaling readouts largely correlative"]},{"year":2008,"claim":"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","pmids":["18504303","18794121"],"confidence":"High","gaps":["Mechanism setting differential mFlt-1 vs sFlt-1 expression unresolved","CXCL12 induction pathway downstream of FLT1 incomplete"]},{"year":2008,"claim":"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","pmids":["18931684"],"confidence":"High","gaps":["Generalizability of the NFAT/TEM8 axis to normal endothelium unclear"]},{"year":2009,"claim":"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","pmids":["19302266","20080765"],"confidence":"Medium","gaps":["Receptor-proximal link to Rab4A unspecified","Pericyte ablation mechanism not molecularly defined"]},{"year":2010,"claim":"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","pmids":["21752276","21139021"],"confidence":"High","gaps":["In vivo relevance of autocrine sFlt-1 antagonism not directly tested","Quantitative thresholds for the switch unknown"]},{"year":2011,"claim":"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","pmids":["21212275","21460247","21389833"],"confidence":"Medium","gaps":["Structural basis of RACK1/PTK7 binding not determined","Hierarchy among PI3K/Akt-Rac1 effectors not resolved"]},{"year":2013,"claim":"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","pmids":["23303818"],"confidence":"High","gaps":["Direct transcriptional targets linking calcineurin to Flt1 not detailed"]},{"year":2014,"claim":"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","pmids":["25387128"],"confidence":"High","gaps":["Relative contribution of shedding versus intronic polyadenylation to soluble FLT1 pools in vivo unresolved"]},{"year":2017,"claim":"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","pmids":["28246215","29146905","30316329","29263797"],"confidence":"High","gaps":["Mechanism of Akt/ERK-independent FLT1 migration signaling unidentified","How pericyte FLT1 shapes local VEGF gradients quantitatively unresolved"]},{"year":2020,"claim":"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","pmids":["31934626","38261818"],"confidence":"Medium","gaps":["Direct FLT1-proximal signaling in keratinocytes versus decoy role not separated","GRK2-PPARγ-Flt1 axis specificity to disease context unclear"]},{"year":null,"claim":"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.","evidence":"No direct experimental resolution in the available corpus","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,26,29]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,6,10]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,5,14,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,5,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[29,31]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[14,15,18]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9,25,26,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,14,18,30,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,28,33,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,19,27,34,35,36]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[22,29]}],"complexes":[],"partners":["KDR","NRP1","PTK7","RACK1","SHCB","ADAM10","ADAM17","CBL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17948","full_name":"Vascular endothelial growth factor receptor 1","aliases":["Fms-like tyrosine kinase 1","FLT-1","Tyrosine-protein kinase FRT","Tyrosine-protein kinase receptor FLT","FLT","Vascular permeability factor receptor"],"length_aa":1338,"mass_kda":150.8,"function":"Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (By similarity). May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275) Phosphorylates PLCG May function as decoy receptor for VEGFA May function as decoy receptor for VEGFA May function as decoy receptor for VEGFA Has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P17948/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FLT1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FLT1","total_profiled":1310},"omim":[{"mim_id":"621227","title":"OLEOYL-ACP HYDROLASE; OLAH","url":"https://www.omim.org/entry/621227"},{"mim_id":"614670","title":"PERIPARTUM CARDIOMYOPATHY, SUSCEPTIBILITY TO; PPCM","url":"https://www.omim.org/entry/614670"},{"mim_id":"611514","title":"WNT LIGAND SECRETION MEDIATOR; WLS","url":"https://www.omim.org/entry/611514"},{"mim_id":"609673","title":"PLATELET-DERIVED GROWTH FACTOR D; PDGFD","url":"https://www.omim.org/entry/609673"},{"mim_id":"606410","title":"ANTHRAX TOXIN RECEPTOR 1; ANTXR1","url":"https://www.omim.org/entry/606410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":394.3}],"url":"https://www.proteinatlas.org/search/FLT1"},"hgnc":{"alias_symbol":["VEGFR1"],"prev_symbol":["FLT"]},"alphafold":{"accession":"P17948","domains":[{"cath_id":"2.60.40.10","chopping":"34-130","consensus_level":"high","plddt":80.8205,"start":34,"end":130},{"cath_id":"2.60.40.10","chopping":"145-225","consensus_level":"high","plddt":91.4404,"start":145,"end":225},{"cath_id":"2.60.40.10","chopping":"232-330","consensus_level":"high","plddt":84.8219,"start":232,"end":330},{"cath_id":"2.60.40.10","chopping":"339-425","consensus_level":"high","plddt":89.1862,"start":339,"end":425},{"cath_id":"2.60.40.10","chopping":"432-473_488-554","consensus_level":"high","plddt":85.5711,"start":432,"end":554},{"cath_id":"2.60.40.10","chopping":"560-654","consensus_level":"high","plddt":84.0164,"start":560,"end":654},{"cath_id":"2.60.40.10","chopping":"669-750","consensus_level":"high","plddt":88.2221,"start":669,"end":750},{"cath_id":"3.30.200.20","chopping":"809-912","consensus_level":"medium","plddt":80.3772,"start":809,"end":912},{"cath_id":"1.10.510.10","chopping":"915-934_992-1168","consensus_level":"medium","plddt":81.0816,"start":915,"end":1168}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17948","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17948-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17948-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FLT1","jax_strain_url":"https://www.jax.org/strain/search?query=FLT1"},"sequence":{"accession":"P17948","fasta_url":"https://rest.uniprot.org/uniprotkb/P17948.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17948/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17948"}},"corpus_meta":[{"pmid":"7596436","id":"PMC_7596436","title":"Role 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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.\",\n      \"method\": \"Gene targeting (flt-1 null mice), in vivo developmental analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, replicated and widely cited foundational study\",\n      \"pmids\": [\"7596436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Targeted deletion of Flt-1 kinase domain (flt-1 TK-/- mice), in vivo developmental analysis, macrophage migration assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotypic readouts (vascular development and macrophage migration), multiple orthogonal endpoints\",\n      \"pmids\": [\"9689083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Radioligand binding assay (125I-VEGF competition and 125I-PlGF direct binding), receptor autophosphorylation assay, receptor-expressing NIH3T3 cells\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding and kinase activity assays with direct ligand-receptor binding, replicated by multiple subsequent studies\",\n      \"pmids\": [\"8822205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR, Northern analysis, immunoprecipitation; cultured glomerular mesangial cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — expression in non-endothelial cells confirmed by multiple methods in single lab\",\n      \"pmids\": [\"7726838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Northern analysis, in situ hybridization, Western analysis, receptor phosphorylation assay, cell proliferation assay in isolated and cultured uterine smooth muscle cells\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-level evidence: receptor expression, phosphorylation, and proliferative response all demonstrated in same primary cell system\",\n      \"pmids\": [\"9042161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Baculovirus expression of deletion mutants, ligand binding assays, COS cell expression of kinase mutants, endothelial cell proliferation inhibition assay\",\n      \"journal\": \"Japanese journal of cancer research : Gann\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic domain deletion mutagenesis combined with binding assays and functional readout in single study\",\n      \"pmids\": [\"9369935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Retroviral mutagenesis to generate constitutively active Flt-1, cell transformation assays, cytokine-independence assay, morphology in basement membrane matrix\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-based functional assays, single lab, gain-of-function approach\",\n      \"pmids\": [\"9632135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, site-directed mutagenesis, domain-deletion binding studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast two-hybrid with domain mutagenesis, single lab\",\n      \"pmids\": [\"9790910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"BIAcore surface plasmon resonance, in vitro binding experiments with purified proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro binding with quantified Kd, domain-mapping, single lab\",\n      \"pmids\": [\"10842181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Blocking monoclonal antibodies against Flt-1 and KDR, actin staining, Western blot for FAK/paxillin phosphorylation, reporter gene assays in HUVECs\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific blocking antibodies used to dissect receptor-specific signaling, multiple readouts, single lab\",\n      \"pmids\": [\"10865839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Flt-1 TK-/- mice, tumor implantation experiments with PlGF-2- or VEGF-overexpressing Lewis lung carcinoma cells, tumor volume and vessel density measurements\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with in vivo tumor angiogenesis readout, ligand specificity control included\",\n      \"pmids\": [\"11221852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Tissue microarray, nuclear fractionation, siRNA knockdown, pathway inhibitors, ubiquitination assays in endothelial cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, siRNA, pathway inhibitors), single lab\",\n      \"pmids\": [\"19834490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"CD34+ hematopoietic progenitor cell differentiation assays, soluble Flt-1 blocking experiments, exogenous VEGF/PlGF addition, flow cytometry for polyploidization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking assay combined with gain-of-function, defined cellular phenotype, single lab\",\n      \"pmids\": [\"12406876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of PlGF, receptor binding assays, cell surface activation assays, in vitro tube formation, in vivo chorioallantoic membrane assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis combined with binding and functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"15272021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Flt-1-/- ES cell-derived vascular cultures, time-lapse GFP imaging, in vivo dorsal aorta analysis, sflt-1 transgene rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined morphogenetic phenotype, in vivo validation, and rescue experiment with isoform specificity\",\n      \"pmids\": [\"14982871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"RNase protection assay, Northern blot, 3' RACE, mutagenesis of polyadenylation signal sequences in reporter assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods including mutagenesis-validated reporter assay, defining molecular mechanism of sFlt1 generation\",\n      \"pmids\": [\"17615362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Adenoviral HO-1 overexpression, HO-1-/- mice, selective receptor ligands (VEGF-E, PlGF), VEGFR2-specific inhibitor, CORM-2 treatment, ELISA\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches including genetic KO, pharmacological inhibition, and selective ligands in same study\",\n      \"pmids\": [\"17389265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Flt-1+/- knockout mice, isolated working heart ischemia/reperfusion protocol, Western blot for signaling intermediates, RT-PCR for HO-1\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cardiac phenotype and multiple molecular readouts, single lab\",\n      \"pmids\": [\"17448895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Flt-1 isoform transgene rescue in ES cell-derived flt-1-/- vessels, Flk-1 Y1173 phosphorylation analysis, reporter gene expression analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue with isoform-specific transgenes, multiple orthogonal readouts, mechanistic dissection of sFlt-1 vs mFlt-1 function\",\n      \"pmids\": [\"18504303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Bone marrow transplantation of Flt-1 TK-/- cells into irradiated recipients, orthotopic glioma implantation, tumor volume and vessel density measurement, CXCL12 ELISA\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bone marrow chimera approach with cell-type-specific KO, multiple tumor models and molecular readouts\",\n      \"pmids\": [\"18794121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Gene expression profiling, NFAT reporter assays, blocking antibodies, soluble VEGFR1 rescue experiments, mutational analysis of VEGFR2 and TEM8\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, rescue experiments, antibody blockade, mutational analysis), mechanistic pathway established in primary cells\",\n      \"pmids\": [\"18931684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Systemic VEGF/PlGF delivery by protein implantation, tumor models, adenoviral vectors; VEGFR1-specific neutralizing antibody (MF1); pericyte quantification by immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo receptor-specific blockade with quantitative pericyte readout, single lab\",\n      \"pmids\": [\"20080765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"VEGFR1 activation in endothelial cells, Rab4A siRNA knockdown, αvβ3 integrin trafficking assay, fibronectin polymerization assay, organotypic angiogenesis model\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"19302266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, adenoviral overexpression, VEGFR-2 phosphorylation assays, eNOS phosphorylation, tube formation assay, cell migration assay in HUVECs\",\n      \"journal\": \"Vascular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both gain- and loss-of-function with multiple molecular endpoints, single lab\",\n      \"pmids\": [\"21752276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal blocking approaches (recombinant protein, antibodies, kinase inhibitor, siRNA) all confirm same mechanism\",\n      \"pmids\": [\"21139021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assay, siRNA knockdown of RACK1, cell migration assay, PI3K/Akt/Rac1 pathway analysis in Flt-1-expressing AG1-G1-Flt1 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus siRNA with pathway analysis, single lab\",\n      \"pmids\": [\"21212275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — SPR-confirmed direct interaction, siRNA KD with defined molecular and cellular phenotype, in vivo validation\",\n      \"pmids\": [\"21460247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of VEGFR1, VEGFR2-specific kinase inhibitor (PTKi-II), PKC isoform siRNA/inhibitors, Matrigel tube formation assay, in vivo allograft B16/F10 melanoma\",\n      \"journal\": \"Melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific siRNA plus isoform-specific PKC targeting, in vivo confirmation, single lab\",\n      \"pmids\": [\"21389833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional deletion of Wntless/GPR177 and CNB1 in macrophages, myeloid-specific Flt1 conditional KO, wound angiogenesis quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO alleles with defined pathway epistasis and quantitative phenotypic readouts\",\n      \"pmids\": [\"23303818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic gain- and loss-of-function mutagenesis and knockdown experiments with multiple molecular mechanisms elucidated in single study\",\n      \"pmids\": [\"25387128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Pericyte-specific conditional Vegfr1 KO mice, pharmacological pericyte depletion, intraocular VEGF-A injection, retinal vascular morphometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with phenotypic recapitulation by orthogonal pharmacological approach\",\n      \"pmids\": [\"29146905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro complementary approaches with isoform-specific manipulation and live-imaging readouts\",\n      \"pmids\": [\"28246215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts and signaling pathway analysis, single lab in primary cells\",\n      \"pmids\": [\"30316329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Computational signaling model, pharmacological pathway inhibitors (PLCγ and PI3K inhibitors), macrophage migration and proliferation assays\",\n      \"journal\": \"NPJ systems biology and applications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — empirical validation of computational model with pathway inhibitors, single lab\",\n      \"pmids\": [\"29263797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional epidermal-specific KO of Flt1 and Nrp1, psoriasis mouse models, transcriptional and chromatin profiling (ATAC-seq/RNA-seq), anti-Nrp1 antibody treatment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models with orthogonal pharmacological confirmation, genome-scale mechanistic profiling\",\n      \"pmids\": [\"31934626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VEGFR1 tyrosine kinase signaling promotes pulmonary fibrosis; the review synthesizes genetic and pharmacological evidence that blocking VEGFR1-TK signal is beneficial in fibrosis models.\",\n      \"method\": \"Review/synthesis of genetic and pharmacological studies (Flt-1 TK-/- models and TK inhibitor studies)\",\n      \"journal\": \"Inflammation and regeneration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper synthesizing prior evidence without new primary mechanistic experiments\",\n      \"pmids\": [\"34082837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with reporter assay and co-IP to define GRK2-PPARγ-Flt1 axis, multiple methods, single lab\",\n      \"pmids\": [\"38261818\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FLT1/VEGFR1 is a high-affinity receptor for VEGF-A, PlGF, and VEGF-B whose extracellular domain acts as a VEGF decoy (via both membrane-bound and alternatively spliced soluble forms, sFlt-1, generated by intronic polyadenylation) to negatively regulate physiological angiogenesis during embryogenesis, while its tyrosine kinase domain—though weaker than VEGFR2—mediates positive signaling for macrophage/myeloid cell migration (via PI3K/Akt-Rac1/RACK1 and PLCγ pathways), endothelial cell migration and anastomosis (modulated by mFlt-1 spatial gradient), pericyte-dependent control of sprouting, and pathological angiogenesis under conditions of excess Flt-1-specific ligands; ectodomain shedding is mediated by ADAM10/ADAM17 and regulated by VEGFR2 heterodimerization, PKC, and c-CBL-mediated ubiquitination, while sFlt-1 further acts as an autocrine regulator that sensitizes endothelial cells to inflammatory stimuli by antagonizing VEGFR2 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #2]. 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 [#5]. 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 [#1]. 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 [#14, #15, #18]. 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 [#10, #25, #26, #33, #8, #31]. FLT1 also controls vascular sprouting non-cell-autonomously through expression in pericytes [#30], and amplifies pathological angiogenesis in tumors, psoriatic keratinocytes, and arthritic synovium [#19, #34, #36]. Ectodomain shedding of membrane Flt-1 is executed by ADAM10/ADAM17, enhanced by PKC and limited by VEGFR2 heterodimerization and c-CBL-mediated ubiquitination [#29]; sFlt-1 additionally acts as an autocrine antagonist of VEGFR2 that sensitizes endothelial cells to inflammatory stimuli [#23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"flt-1 null mouse gene targeting with in vivo developmental analysis\",\n      \"pmids\": [\"7596436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the defect reflects loss of signaling or loss of VEGF sequestration\", \"Molecular mechanism of disorganized vascular assembly unspecified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Radioligand binding and receptor autophosphorylation assays in receptor-expressing NIH3T3 cells\",\n      \"pmids\": [\"8822205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling consequences of PlGF binding not addressed\", \"Did not establish in vivo ligand selectivity\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"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.\",\n      \"evidence\": \"Deletion-mutant baculovirus/COS expression with binding and endothelial proliferation assays\",\n      \"pmids\": [\"9369935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test the natural soluble isoform in vivo\", \"Structural basis of high affinity not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended FLT1 function beyond endothelium by showing functional VEGF-responsive receptors on mesangial and uterine smooth muscle cells.\",\n      \"evidence\": \"Expression, phosphorylation, and proliferation assays in primary non-endothelial cells\",\n      \"pmids\": [\"7726838\", \"9042161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of FLT1 in these cell types in vivo not established\", \"Downstream pathway not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved the kinase-versus-decoy question genetically: the ectodomain alone suffices for vascular development while the kinase domain is required specifically for macrophage migration.\",\n      \"evidence\": \"Flt-1 kinase-domain deletion (TK-/-) mice with developmental and macrophage migration readouts\",\n      \"pmids\": [\"9689083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify downstream effectors of kinase signaling\", \"Did not address pathological angiogenesis context\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated the FLT1 kinase has intrinsic transforming and morphogenic potential when constitutively activated, and identified Sck/Shc as a kinase-dependent adaptor.\",\n      \"evidence\": \"Constitutively active chimera transformation assays; yeast two-hybrid with mutagenesis\",\n      \"pmids\": [\"9632135\", \"9790910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sck interaction not validated in endothelial cells\", \"Relevance of forced activation to native signaling unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"SPR binding with purified proteins; receptor-specific blocking antibodies in HUVECs\",\n      \"pmids\": [\"10842181\", \"10865839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of FLT1-NP1 competition not tested in vivo\", \"Homodimer signaling readouts partly correlative\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"TK-/- mice with PlGF-2 tumor models; tissue arrays, fractionation, siRNA, ubiquitination assays\",\n      \"pmids\": [\"11221852\", \"19834490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear localization function mechanistically unresolved\", \"Survival pathway details incomplete\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated autocrine VEGF/Flt1 signaling supports hematopoietic (megakaryocyte) maturation, broadening FLT1's roles beyond vessel patterning.\",\n      \"evidence\": \"CD34+ differentiation assays with soluble Flt-1 blockade and exogenous ligand\",\n      \"pmids\": [\"12406876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal signaling in megakaryocytes not defined\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the molecular determinants of PlGF-FLT1 engagement and clarified that the soluble isoform positively regulates sprouting by spatially limiting VEGF-A.\",\n      \"evidence\": \"PlGF site-directed mutagenesis with functional assays; flt-1-/- vascular cultures with sflt-1 transgene rescue\",\n      \"pmids\": [\"15272021\", \"14982871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative spatial model of ligand gradients not yet formalized\", \"Full-length isoform's distinct contribution unresolved here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"RACE/RPA/reporter mutagenesis; HO-1 KO/CORM-2 with selective ligands; Flt-1+/- ischemic heart studies\",\n      \"pmids\": [\"17615362\", \"17389265\", \"17448895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific regulation of intronic polyadenylation not mapped\", \"Cardiac signaling readouts largely correlative\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Isoform-specific transgene rescue with Flk-1 phosphorylation mapping; TK-/- bone marrow chimeras in glioma\",\n      \"pmids\": [\"18504303\", \"18794121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism setting differential mFlt-1 vs sFlt-1 expression unresolved\", \"CXCL12 induction pathway downstream of FLT1 incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed FLT1 transcriptional regulation (NFAT/β1-integrin/TEM8/VEGFR2) controls VEGFR2 activity, with low FLT1 driving constitutive VEGFR2 signaling in hemangioma.\",\n      \"evidence\": \"Expression profiling, NFAT reporters, blocking antibodies, soluble VEGFR1 rescue, mutational analysis\",\n      \"pmids\": [\"18931684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of the NFAT/TEM8 axis to normal endothelium unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Rab4A siRNA with integrin trafficking/fibronectin assays; VEGFR1-specific antibody (MF1) in vivo pericyte quantification\",\n      \"pmids\": [\"19302266\", \"20080765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal link to Rab4A unspecified\", \"Pericyte ablation mechanism not molecularly defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established sFlt-1 as an autocrine antagonist of VEGFR2 that restrains endothelial migration/eNOS and sensitizes endothelium to inflammatory TNF-α.\",\n      \"evidence\": \"siRNA/overexpression and multiple receptor-blocking approaches with adhesion molecule and signaling readouts in HUVECs\",\n      \"pmids\": [\"21752276\", \"21139021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of autocrine sFlt-1 antagonism not directly tested\", \"Quantitative thresholds for the switch unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified direct cytoplasmic and co-receptor partners (RACK1, PTK7) required for FLT1 kinase signaling and migration, and a PKCα-dependent role in vasculogenic mimicry.\",\n      \"evidence\": \"In vitro binding, SPR, siRNA with pathway analysis and migration/angiogenesis assays; PKC-isoform targeting with melanoma models\",\n      \"pmids\": [\"21212275\", \"21460247\", \"21389833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of RACK1/PTK7 binding not determined\", \"Hierarchy among PI3K/Akt-Rac1 effectors not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined an upstream transcriptional control circuit (Wnt-Calcineurin) that activates myeloid Flt1 to suppress wound angiogenesis, with myeloid Flt1 deletion accelerating repair.\",\n      \"evidence\": \"Conditional Wntless/CNB1 and myeloid-specific Flt1 KO with wound angiogenesis quantification\",\n      \"pmids\": [\"23303818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets linking calcineurin to Flt1 not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the protease and regulatory machinery of ectodomain shedding: ADAM10/ADAM17 cleavage controlled by PKC, VEGFR2 heterodimerization, and c-CBL ubiquitination.\",\n      \"evidence\": \"Metalloprotease inhibitors, ADAM overexpression/siRNA, deletion mutants, VEGFR2 co-expression, c-CBL knockdown in HUVEC/HEK293\",\n      \"pmids\": [\"25387128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of shedding versus intronic polyadenylation to soluble FLT1 pools in vivo unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Isoform-selective manipulation with live imaging; pericyte-specific conditional KO with retinal morphometry; FLT1/KDR siRNA in primary placental ECs\",\n      \"pmids\": [\"28246215\", \"29146905\", \"30316329\", \"29263797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Akt/ERK-independent FLT1 migration signaling unidentified\", \"How pericyte FLT1 shapes local VEGF gradients quantitatively unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Epidermal conditional KO with ATAC/RNA-seq; GRK2 conditional KO with reporter and co-IP in arthritis model\",\n      \"pmids\": [\"31934626\", \"38261818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FLT1-proximal signaling in keratinocytes versus decoy role not separated\", \"GRK2-PPARγ-Flt1 axis specificity to disease context unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No direct experimental resolution in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 26, 29]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 6, 10]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 5, 14, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [29, 31]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [14, 15, 18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9, 25, 26, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 14, 18, 30, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 28, 33, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 19, 27, 34, 35, 36]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [22, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KDR\", \"NRP1\", \"PTK7\", \"RACK1\", \"SHCB\", \"ADAM10\", \"ADAM17\", \"CBL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}