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FLASH GENE
Symbol FLT1 contributors: mct - updated : 21-09-2016
HGNC name fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)
HGNC id 3763
Location 13q12.3      Physical location : 28.874.482 - 29.069.265
Synonym name
  • VEGF receptor 1
  • Fms-like tyrosine kinase 1
  • tyrosine-protein kinase FRT
  • tyrosine-protein kinase receptor FLT
  • vascular endothelial growth factor receptor 1
  • Synonym symbol(s) FLT, FRT, VEGFR1, SFLT1, VEGFR1-TK
    EC.number 2.7.10.1
    DNA
    TYPE functioning gene
    SPECIAL FEATURE arranged in tandem
    text linked in a head to tail configuration with FLT3 and separated by about 150 kb
    STRUCTURE 194.78 kb     30 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    text structure one CpG island
    MAPPING cloned Y linked N status confirmed
    Physical map
    LOC387914 13 similar to WGAR9166 RNF6 13q12 ring finger protein (C3H2C3 type) 6 CDK8 13q12 cyclin-dependent kinase 8 WASF3 13q12 WAS protein family, member 3 LOC390389 13 similar to ribosomal protein S3a; 40S ribosomal protein S3a; v-fos transformation effector protein 1 GPR12 13q12 G protein-coupled receptor 12 USP12 5q33-q34 ubiquitin specific protease 12 RPL21 13pter-p13 ribosomal protein L21 LOC254109 13q12.2 similar to MGC53580 protein GTF3A 13q12.3-q13.1 general transcription factor IIIA MTIF3 13q12.2 mitochondrial translational initiation factor 3 PDZRN1 13q12.2 PDZ domain containing ring finger 1 MGC9850 13q12.2 hypothetical protein MGC9850 POLR1D 13q12.2 polymerase (RNA) 1 polypeptide D, 16kDa GSH1 13q12.13 GS homeobox 1 IPF1 13q12.1 insulin promoter factor 1, homeodomain transcription factor LOC387915 13 hypothetical gene supported by AK000246 CDX2 13q12-q13 caudal type homeo box transcription factor 2 FLT3 13q12 fms-related tyrosine kinase 3 LOC390390 13 similar to chromosome 7 open reading frame 17 protein; 16.7kD protein LOC390391 13 similar to Elongation factor 1-alpha 1 (EF-1-alpha-1) (Elongation factor 1 A-1) (eEF1A-1) (Elongation factor Tu) (EF-Tu) PAN3 13q12.2 PABP1-dependent poly A-specific ribonuclease subunit PAN3 FLT1 13q12 fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor) LOC341784 13q12.3 similar to eukaryotic translation initiation factor 4A1; initiation factor eIF-4A long form C13orf12 13q12.13 chromosome 13 open reading frame 12 LOC283537 13q12.3 hypothetical protein LOC283537 CYP51P2 13 hypothetical protein LOC283537 KIAA0774 13q12.13-q12.2 hypothetical protein LOC283537 SLC7A1 13q12.3 solute carrier family 7 (cationic amino acid transporter, y+ system), member 1 UBL3 13q12-q13 ubiquitin-like 3 MGC2599 13q12.3 hypothetical protein MGC2599 similar to katanin p60 subunit A 1 2599 PRDX2P1 13p12 peroxiredoxin 2 pseudogene 1 UBCH7N2 13q12.3 ubiquitin-conjugating enzyme-like HMGB1 13q12 high-mobility group box 1 LOC390392 13 similar to Protein-tyrosine phosphatase, non-receptor type 2 (T-cell protein-tyrosine phosphatase) (TCPTP) D13S106E 13q12-q14 highly charged protein ALOX5AP 13q12 arachidonate 5-lipoxygenase-activating protein LOC387917 13 LOC387917
    RNA
    TRANSCRIPTS type messenger
    text splice variant SFLT1 (soluble) with high affinity for VEGF
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    30 splicing 7123 150.77 1338 - 1990 2158038
  • also called FLT1
  • type I membrane protein
  • 13 splicing 6499 - 687 . placenta highly . serum 2011 21168388
  • also called sFLT1
  • playing an inhibitory role in angiogenesis
  • soluble protein
  • heterodimerizing with FLK1
  • six N terminal immunoglobulin-like domains
  • inhibiting mitogenic activity of vascular endothelial cell growth factor
  • in hypoxia, endothelial cells displayed nearly a 10-fold increase levels in comparison to normoxia conditions
  • 12 - 1911 - 541 - 2011 21168388
    15 - 2968 - 733 - 2011 21168388
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Endocrineparathyroid   highly
     thyroid   highly
    Nervousnerve   highly
     nervecranial nerve  highly
    Reproductivefemale systemplacenta  predominantly
    Respiratorylung   lowly
    Urinarykidney   moderately
    Visualeyeanterior segmentcornea highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  moderately
    Connectiveadipose  highly
    Epithelialbarrier liningretinal pigment epithelium (RPE) highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmonocyte
    Blood/Hematopoieticplatelet
    Cardiovascularendothelial cell
    Urinarypodocyte Homo sapiens
    cell lineage
    cell lines CLL B cell lines
    fluid/secretion plasma, serum, blood
    at STAGE
    physiological period pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • extracellular segment with seven immunoglobulin-like C2-type domains
  • a unique transmembrane segment TM1
  • a short intracellular juxtamembrane region
  • a split tyrosine-kinase domain
  • a C terminal sequence
  • conjugated GlycoP
    HOMOLOGY
    interspecies homolog to rattus Flt1 (82.47 pc)
    homolog to murine Flt1 (82.04 pc)
    Homologene
    FAMILY
  • protein kinase superfamily
  • Tyr protein kinase family
  • Fms family of receptor tyrosine kinase
  • CSF-1/PDGF receptor subfamily
  • CATEGORY enzyme , receptor membrane tyrosine kinase
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic,vesicle
    intracellular,nucleus
    text
  • a membrane type I protein isoform and a soluble isoform
  • primarily localized in the nucleus of endothelial cells (
  • is primarily located at the basal aspect of podocyte foot processes, adjacent to the slit diaphragm and in endosomes
  • ROBO4 partially colocalizes with FLT1 in endocytic vesicles, whereas SCARB1 shows more extensive colocalization with FLT1 on the surface of podocytes
  • basic FUNCTION
  • inhibitor of VDGF dependent PI3-kinase activation and endothelial cell migration through the juxtamembrane domain
  • functioning as an antagonist of vascular endothelial growth factor
  • playing an essential role in embryonic vasculature, and for preserving the avascular ambit of the cornea
  • acts to promote endothelial tubule branching in an organotypic model of angiogenesis via a mechanism that requires RAB4A and alphavbeta3 Integrin (
  • FLT1 signaling is required for endothelial-cell survival, while KDR regulates capillary tube formation )
  • contribute to vessel maturation by mediating a dialogue between endothelial cells (ECs) and mural cells that leads to blood vessel stabilization
  • axis KDR/FLT1 is implicated in endochondral bone repair
  • in primary endothelial cells, hypoxia stimulates VEGFA and FLT1 expression but decreases KDR levels
  • regulates the VEGF-triggered migration of endothelial cells and macrophages
  • having functions in malignant melanoma-initiating cells that regulates vasculogenic mimicry and associated laminin production, and promote tumor growth
  • regulates the VEGFA-triggered migration of endothelial cells and macrophages
  • autocrine function for sFLT1 to control pericyte behavior
  • promotes attachment and reorganization of the actin cytoskeleton of podocytes
  • VEGFA-induced sFLT1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis
  • sFLT1 plays an essential role in maintaining vascular integrity in the placenta by sequestering excess maternal VEGFA, suggesting that a local increase in VEGFA can trigger placental overexpression of sFLT1, potentially contributing to the development of preeclampsia and other pregnancy complications
  • secreted FLT1 and cleaved FLT1 will tend to have local effects as a VEGFA antagonist when released from cells expressing KDR and more distant effects when released from cells lacking KDR
  • cell cycle regulator CCNA1 in association with FLT1, is required for haematopoietic stem/progenitor cells (HSPC) and their niches to maintain their function and proper interaction
  • appears to play a role in oxidative stress, which promotes apoptosis of trophoblasts and may be an important mechanism in the development of Pre-eclampsia (PE)
  • soluble FLT1, plays a central role in preeclamptic pathophysiology 5)
  • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS
    text positive control of cell proliferation
    PATHWAY
    metabolism
    signaling
  • non-canonical WNT–FLT1 pathway involved in regulation of angiogenesis in myeloid cells
  • a component
  • FLT1 subunits modulate VEGFA activity predominantly by forming heterodimer receptors with KDR subunits and such heterodimers regulate endothelial cell homeostasis
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
    ATP
    protein
  • binding to VEGF, VEGFB, PGF and FLK1
  • NFAT target gene in endothelial cells
  • GNB2L1 (receptor for activated protein kinase C 1) binds to FLT1, and regulates FLT1-mediated cell migration via activation of a PI3K/Akt pathway
  • JMJD6 mediates splicing of FLT1 by interacting with U2AF2
  • VEGFB is a high-affinity FLT1 ligand that, unlike PGF, cannot efficiently induce signaling downstream of FLT1
  • stimulates likely angiogenesis via transactivation of the EGF receptor, which promotes the phosphorylation of FLT1 and activation of SYK independent of VEGFA expression
  • FLT1 is involved in regulating phosphorylation of nephrin (
  • LGALSs vascular permeability through the NRP1/FLT1 complex
  • JMJD6 may play a role in regulating the production of FLT1 in the preeclamptic placenta
  • EPO had enhanced carcinogenesis through increase of EPOR and FLT1 expression, and thereby contributed to tumor development
  • cell & other
    REGULATION
    activated by hypoxia, in primary endothelial cells
    induced by vitronectin
    repressed by fibrin
    Other regulated by PAX3 or PAX3-FOXO1A
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in hemangioma endothelial cells, resulting in VEGF-dependent activation of KDR and downstream signaling pathways
    constitutional     --over  
    in placentas of preeclampsia and HELLP syndrome
    constitutional     --over  
    higher expression in severe preeclampsia or eclampsia than in normal pregnancy
    constitutional     --over  
    in coronary artery disease where cardiac tissue has been subjected to prolonged or chronic hypoxia, increased VEGFR1, thus selecting for non-ischemic in endothelial cells in promoting pro-angiogenic responses including nitric oxide production
    constitutional     --low  
    loss of expression of FLT1, moderate expression of KDR and high concentration of nitrate associated with aneurysm formation
    constitutional     --over  
    concentration of FLT1 in severe preeclampsia is higher compared with normal pregnancy
    constitutional     --over  
    contributes to endothelial injury in in IgA nephropathy (IgAN)
    constitutional     --low  
    decreased expression of FLT1 in decidua and weaker VEGFA and KDR expression in placental villi and decidua may be associated with early pregnancy loss
    constitutional     --low  
    decreased significantly in serum of patients with ALS
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • with PLGF, is an effective biomarker in predicting PE (preeclampsia) during the second trimester, before the clinical onset of PE
  • sFLT1 levels may be an effective biomarker to predict the progression of heart failure in patients with coronary artery disease (CAD)
  • elevated levels of FLT1 are associated with adverse outcomes in stable patients with heart failure
  • FLT1 mRNA expression in maternal blood can be used as a marker to predict the development of fetal growth restriction (FGR), long before a clinical diagnosis is made
  • molecular detection of MAML2 rearrangement combined with FLT1 may be of important clinical value for Primary pulmonary mucoepidermoid carcinoma (PMEC)
  • Therapy target
  • in treating neovascular diseases
  • SystemTypeDisorderPubmed
    cardiovascularaquired 
    potential therapy target in conditions where inducing angiogenesis might be benficial (preeclampsia, wound healing, strocke and heart disease)
    cancer  
    therapeutic potential for FLT1-modifying drugs in cancer pain
    cancerangiogenesis 
    disrupting PGF/FLT1 pathway could modulate endothelial-colony-forming cells (ECFCs)-induced tubulogenesis, the cell type responsible for newly formed vessels
    ANIMAL & CELL MODELS
  • Flk1 disrupted transgenic mice
  • mdx:Flt-1(+/-) adult mice display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice (mdx:utrophin(-/-):Flt-1(+/-) mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin(-/-) mice, which show more severe muscle phenotypes than the mdx mice)
  • loss of normal foot process structure in mice lacking Flt1 results in massive protein leakage into the urine due to disruption of the glomerular permeability barrier, resulting eventually in kidney failure