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FLASH GENE
Symbol KDR contributors: mct - updated : 19-05-2015
HGNC name kinase insert domain receptor (a type III receptor tyrosine kinase)
HGNC id 6307
Location 4q12      Physical location : 55.944.426 - 55.991.762
Synonym name
  • kinase insert domain receptor
  • vascular endothelial growth factor receptor 2
  • CD309 antigen
  • fetal liver kinase-1
  • soluble VEGFR2
  • tyrosine kinase growth factor receptor
  • Synonym symbol(s) FLK1, KDR1, KDR2, VEGFR, VEGFR2, FLK-1, CD309
    EC.number 2.7.10.1
    DNA
    TYPE functioning gene
    STRUCTURE 47.34 kb     30 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    Binding site   transcription factor
    text structure 5'-flanking sequence is rich in G and C residues and contains five Sp1 elements but no TATA consensus sequence
    MAPPING cloned Y linked N status confirmed
    Physical map
    FIP1L1 4q11-q12 FIP1 like 1 (S. cerevisiae) LNX 4q12 ligand of numb-protein X LOC391653 4 hypothetical gene supported by BC057822 CHIC2 4q11-q12 cysteine-rich hydrophobic domain 2 GSH-2 4q11-q12 homeobox protein GSH-2 PDGFRA 4q11-q12 platelet-derived growth factor receptor, alpha polypeptide LOC254938 4q12 hypothetical LOC254938 KIT 4q12 v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog KDR 4q12 kinase insert domain receptor (a type III receptor tyrosine kinase) FLJ13352 4q12 hypothetical protein FLJ13352 TPARL 4q12 TPA regulated locus CLOCK 4q12 clock homolog (mouse) GCPHLP 4q12 likely ortholog of mouse germ cell-specific phosphoducin-like protein Mgcphlp NMU 4q12 neuromedin U SEC3 FLJ13621 4q12 hypothetical protein FLJ13621 KIAA0635 4q12-q13.3 hypothetical protein FLJ13621 KIAA1211 4q12 KIAA1211 protein MRPL22P1 4q12 KIAA1211 protein NRPS998 4q12 2-aminoadipic 6-semialdehyde dehydrogenase PPAT 4q12 phosphoribosyl pyrophosphate amidotransferase PAICS 4q12 phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase SRP72 1q32 signal recognition particle 72kDa LOC132946 4q12 similar to MGC69138 protein LOC391654 4 LOC391654 GLDCP 4q12 glycine dehydrogenase (decarboxylase) pseudogene HOP 4q11-q12 homeodomain-only protein
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    30 - 6055 - 1356 - 1995 7559454
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel   highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell
    cell lineage normal hematopoietic
    cell lines leukemia cell lines HEL, CMK86
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • seven immunoglobulin-like domains
  • a unique transmembrane segment TM1
  • a short intracellular juxtamembrane region
  • a split tyrosine-kinase domain
  • A PEST motif, acting as a dual modulator of KDR, and involved in the degradation and ubiquitination of KDR
  • a C terminal sequence
  • HOMOLOGY
    interspecies homolog to murine Kdr (86.75 pc)
    Homologene
    FAMILY
  • protein kinase superfamily
  • Tyr protein kinase family
  • CSF-1/PDGF receptor subfamily
  • CATEGORY enzyme , signaling growth factor , receptor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    text exhibits both plasma membrane and endosomal localization
    basic FUNCTION
  • vascular endothelial growth factor receptor, receptor tyrosine kinase, that regulates vascular physiology
  • also regulating the migration of early mesodermally derived precursors into a microenvironnement that is permissive for hematopoiesis (marker defining hematopoietic stem cells)
  • playing a crucial role in vasculogenesis and angiogenesis
  • key receptor directly responsible for endothelial cell signaling stimulated by VEGF
  • undergoes ligand-stimulated activation, phosphorylation and ubiquitination linked to proteasome and lysosome-linked degradation
  • involved in regulation of endothelial function (KDR-mediated regulation of endothelial function is dependent on different but specific Rab-mediated GTP hydrolysis activity required for endosomal trafficking)
  • play critical roles in angiogenesis and vascular repair, which are involved in the progress of coronary heart disease
  • 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
  • undertakes a constitutive recycling pathway between the peripheral endosomes and cell surface and this exists in both vascular and non-vascular cells
  • endothelial KDR undergoes constitutive recycling between the plasma membrane and endosomes
  • myocardially produced VEGFA signals through endocardial KDR to stimulate ventricular endocardial cells to undergo angiogenesis that generates coronary arteries
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • heterodimer FLT1/KDR
  • GREM1/KDR axis participates in renal inflammation and could be a novel target for kidney disease
  • 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
    protein
  • interacting with PIM1 (required for endothelial and mural cell differentiation)
  • interacting with VEGFA and PDGFA
  • target of WNT2 signaling in hepatic sinusoidal endothelial cells
  • interaction with FLNB, a scaffolding protein connecting also VAV2and RAC1 proteins for endothelial cell motility
  • interacts with TMEM204 (TMEM204 attenuates the transcription factor CREB phosphorylation via FLT4 and KDR
  • binds directly to KL and TRPC1 and strengthens the association to promote their cointernalization (
  • interaction with NANOG (necessary and sufficient role of NANOG in inducing the transcription of KDR to regulate the angiogenic phenotypes of ECs (endothelial cells)
  • new role for THBS1 and CD36 in the activation of the KDR signaling pathway that requires SYK
  • addition of OPRK1 agonists to KDR vascular progenitors inhibited endothelial cells differentiation and vascular formation
  • interacing with LGALS3 (modulates cell surface expression and activation of KDR in endothelial cells
  • substantial DLL4 expression is maintained in the absence of KDR, while the FLT4 protein levels are strongly reduced
  • both NOTCH1 and KDR modulate FLT4 protein and activation levels independently and in opposite directions
  • induces SRC signaling and vascular permeability in vivo via the adaptor protein SH2D2A
  • MCAM interacts directly with KDR on endothelial cells
  • MYO1C is an important mediator of VEGF-induced KDR delivery to the cell surface and plays a role in angiogenic signaling
  • C1GALT1C1 was able to regulate VEGF-triggered phosphorylation of KDR
  • GREM1 binds to vascular endothelial growth factor receptor-2 (KDR) in endothelial cells to induce angiogenesis
  • TBX1 down regulates the expression of KDR, during embryonic development
  • CLEC14A acts in vascular homeostasis by fine-tuning KDR and FLT4 signaling in ECs, suggesting its relevance in the pathogenesis of angiogenesis-related human disorders
  • RABEP2, a RAB-effector protein implicated in arteriogenesis, modulates KDR trafficking
  • cell & other
    REGULATION
    activated by VEGF in cooperation with integrin alpha V (ITGAV) beta 3 (ITGB3)
    IL6
    CCL23 ( involved in potentiation of VEGF-induced proliferation and migration in human umbilical vein endothelial cells HUVECs, an indirect mechanism for the angiogenic responses of endothelial cells induced by CCL23)
    EFNB2 (EFNB2 reverse signalling through PDZ interactions as a positive regulator of KDR trafficking and signalling to control endothelial tip-cell-mediated vessel sprouting in physiological and pathological settings)
    inhibited by inhibition of KDR not only prevents assembly of the receptor complex PDGFRB/KDR but also restores angiogenesis in tissues exposed to both VEGFA and PDGFA
    Other decursin supresses KDR activation and thus inhibits VEGF-mediated inner blood-retinal barrier breakdown
    regulated by EFNB2 (ephrin-B2 reverse signalling through PDZ interactions as a positive regulator of KDR trafficking and signalling to control endothelial tip-cell-mediated vessel sprouting in physiological and pathological settings)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional somatic mutation      
    in juvenile hemangioma
    tumoral     --over  
    in invasive ovarian cancer
    tumoral   amplification    
    coamplification of PDGFRA or KDR with KIT may be clinically useful novel molecular markers in medulloblastomas and primitive neuroectodermal tumors
    constitutional     --low  
    in coronary artery disease where cardiac tissue has been subjected to prolonged or chronic hypoxia
    constitutional     --low  
    loss of expression of FLT1, moderate expression of KDR and high concentration of nitrate associated with aneurysm formation
    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
    Susceptibility to coronary heart disease
    Variant & Polymorphism SNP SNP1192 and SNP1719 associated with risk of coronary heart disease
    Candidate gene early marker for endothelial cell progenitors
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    tumor  
    blocking EFNB2 signaling in tumors might represent an intriguing strategy to interfere simultaneously with both KDR and FLT4 function that could be used as an alternative or combinatorial anti-angiogenic treatment for tumor therapy
    tumor  
    blocking ephrin-B2 reverse signaling may be an attractive alternative or combinatorial anti-angiogenic therapy strategy to disrupt KDR function in tumour angiogenesis
    tumor  
    inhibition of tyrosine phosphorylation of KDR by wogonin, correlated with a significant decrease in VEGF-triggered phosphorylated forms of ERK, AKT1 and MAPK14, associated with suppression of tumor growth
    ANIMAL & CELL MODELS