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FLASH GENE

Symbol

FLT4

contributors: mct - updated : 14-10-2014

HGNC name	fms-related tyrosine kinase 4
HGNC id	3767

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	HLMN1 hereditary lymphedema I, type 1 PCLD primary congenital lymphedema
Location	5q35.3      Physical location : 180.028.506 - 180.076.624
Synonym name	vascular endothelial growth factor receptor 3 (VEGFR3)
	tyrosine-protein kinase receptor FLT4
	soluble VEGFR3 variant 1, 2, 3
	vascular endothelial growth factor receptor 3
Synonym symbol(s)	VEGFR3, PCL, FLT41, LMPH1A
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	48.12 kb     30 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   enhancer
text structure	promoter control endothelial cell specific transcription of downstream reporter genes

MAPPING

cloned

Y

linked

N

status

confirmed

Map	see ADRB2 , DRD1

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_182925 30 splicing 5857 NP_891555 152.63 1363 - 2001 11479678 a 32 exons variant containing exon 1b (shorter than 1a) lacking exon 30 NM_002020 30 splicing 4534 NP_002011 145.6 1298 - 2001 11479678 a 30 exons variant containing exon 1a (longer than 1b) lacking C terminal domain from exon 31 to 33 sVEGFR-3 - - - - - - 2013 23476047 truncated isoform, soluble critical for corneal alymphaticity binds and sequesters VEGFC, thereby blocking signaling through FLT4 and suppressing lymphangiogenesis induced by VEGFC

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 heart       highly Nervous brain hindbrain cerebellum     Homo sapiens Fetal   brain forebrain       Homo sapiens Fetal Reproductive male system prostate     highly Respiratory lung       highly Skeleton           Homo sapiens Adult   axial skeleton skull face mandible   Homo sapiens Fetal Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Skeleton osteoblast Homo sapiens Adult Skeleton osteoblast Homo sapiens Fetal

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text	all vessels, placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	seven Ig-like extracellular domains
	a transmembrane segment (1TM)
	a cytoplasmic kinase domain

HOMOLOGY

interspecies	homolog to rattus Flt4 (86.72 pc)
	homolog to murine Flt4 (87.09 pc)

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family
	CSF-1/PDGF receptor subfamily

CATEGORY

regulatory , protooncogene , signaling , receptor membrane

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nucleus

basic FUNCTION	receptor tyrosine kinase, class V, involved in lymphatic vascular function, regulating angiogenesis and vasculogenesis
	crucial role for FLT4 in the regulation of sprouting in endothelial cells with low NOTCH1 signalling activity
	its activity is pro-angiogenic in endothelial cells with low or no NOTCH1 signalling activity
	directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis
	might represent a specific signal for ectomesenchymal lineage differentiation during early human development
	FLT4 with its cognate ligand vascular endothelial growth factor C (VEGFC), is a major mediator of lymphangiogenesis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

cardiovascular

PATHWAY

metabolism

signaling

VEGFC/FLT4 signaling pathway is essential for lymphangiogenesis (the formation of lymphatic vessels from pre-existing vasculature) during embryonic development, tissue regeneration and tumor progression

a component

RSPO1-WNT-VEGFC-FLT4 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis

INTERACTION

DNA

RNA

small molecule

protein	VEGFC
	FIGF (VEGFD)
	interaction between NRP2 and FLT4 mediates proper lymphatic vessel sprouting in response to VEGFC
	interacts with TMEM204 (TMEM204 attenuates the transcription factor CREB phosphorylation via FLT4 and KDR
	macrophage-derived VEGFC activates FLT4 in tip cells to reinforce NOTCH signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts
	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
	interaction between COL18A1 short peptide and FLT4
	VEGFC and its receptor FLT4 mediate lymphangiogenesis
	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

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

HLMN1 , PCLD

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional somatic mutation       in juvenile hemangioma tumoral     --over   in prostate cancer cells (increases the risk of biochemical recurrence in prostate cancer patients treated by radical prostatectomy)

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer angiogenesis   blocking EFNB2 signaling in tumours 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 tumour therapy

ANIMAL & CELL MODELS