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FLASH GENE

Symbol

KDR

contributors: mct - updated : 19-05-2017

HGNC name	kinase insert domain receptor (a type III receptor tyrosine kinase)
HGNC id	6307

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002253 30 - 6055 NP_002244 - 1356 - 1995 7559454

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       highly

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial 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
	mitochondrial UQCRB positively regulates KDR signaling in Endothelial cells
	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
	JAM3 plays an important role in maintaining KDR expression to promote RPE cell survival under oxidative stress
	RABEP2, a RAB-effector protein implicated in arteriogenesis, modulates KDR trafficking
	VEGFA up-regulates MUC5AC expression and RHOA activation by interaction with KDR

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed 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