FLT4 fms-related tyrosine kinase 4 [Homo sapiens] - Gene

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Summary

Official Symbol: FLT4provided by HGNC
Official Full Name: fms-related tyrosine kinase 4provided by HGNC
Primary source: HGNC:3767
See related: Ensembl:ENSG00000037280; HPRD:00636; MIM:136352; Vega:OTTHUMG00000130931
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PCL; FLT41; LMPH1A; VEGFR3
Summary: This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]

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Genomic context

Location :: 5q35.3

Sequence :: Chromosome: 5; NC_000005.9 (180028506..180076624, complement)

See FLT4 in Epigenomics, MapViewer

Chromosome 5 - NC_000005.9 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

The recombinant lentivirus particles were able to remarkably suppress VEGFR-3 expression, regulate the cell cycle, inhibit proliferation and induce apoptosis in the MKN45 cell lines.
Title: Effect of lentivirus-mediated shRNA targeting VEGFR-3 on proliferation, apoptosis and invasion of gastric cancer cells.
Suggest that miR-1236 may function as a negative regulator of VEGFR-3 signaling during inflammatory lymphangiogenesis.
Title: Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis.
VEGF-A plays a role in the occurrence of OHSS, and the amount of biologically available VEGF-A is modulated by sVEGF-R1, R2 and R3
Title: Ovarian hyperstimulation syndrome is correlated with a reduction of soluble VEGF receptor protein level and a higher amount of VEGF-A.
Data show that normal thyroid follicular cells express VEGFRs 1, 2, and 3.
Title: Expression of receptors for VEGFs on normal human thyroid follicular cells and their role in follicle formation.
The correlation between VEGFR-3 and the Gleason score was high in prostate cancer.
Title: [Correlation of the expressions of VEGF-C and VEGFR-3 to the pathological grade of prostate cancer].
Strong expression of VEGF-C and VEGFR-3 in gastrointestinal stromal tumors was not correlated with the clinical parameters of aggressiveness, nor with high lymphatic vessel density.
Title: Lymphangiogenic VEGF-C and VEGFR-3 expression in genetically characterised gastrointestinal stromal tumours.
LYVE-1, VEGFR-3 and CD44 all play an important role in lymphangiogenesis, invasion and metastasis
Title: Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer.
the effects of vegfc/VEGFR3 on the progression of tumor cells to form lymph node metastases occur primarily under an hypoxic tumor microenvironment.
Title: Suppression of vascular endothelial growth factor receptor 3 (VEGFR3) and vascular endothelial growth factor C (VEGFC) inhibits hypoxia-induced lymph node metastases in cervix cancer.
Macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.
Title: VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.
There is a close relationship of laryngeal squamous cell carcinomas with the expression of VEGF-C and VEGFR-3.
Title: [Relationships of human laryngeal squamous cell carcinomas with the expression of VEGF-C and VEGFR-3].

Submit: New GeneRIF Correction See all (95)

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Phenotypes

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Hemangioma, capillary infantile, somatic

MIM: 602089

Milroy disease is characterized by lower-limb lymphedema, present at birth as pedal edema or developing soon after. Occasionally it develops later in life. The severity of edema shows both inter- and intrafamilial variability. Swelling is usually bilateral but can be asymmetric. The degree of edema can progress but in some instances can improve, particularly in early years. Other features sometimes associated with Milroy disease include hydrocele (37% of males), prominent veins (23%), upslanting toenails (14%), papillomatosis (10%), and urethral abnormalities in males (4%). Cellulitis, which can damage the lymphatic vessels, occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females.

Diagnosis Testing

Milroy disease is diagnosed by clinical findings and confirmed by molecular genetic testing. Lymphoscintigraphy can be performed; the characteristic finding is lack of uptake of radioactive colloid in the ilioinguinal lymph nodes caused by a paucity of lymphatic vessels or abnormal function of the vessels in the lower limbs. Molecular genetic testing for FLT4 (VEGFR3), the only gene known to be associated with Milroy disease, is available on a clinical basis.

Genetic Counseling

Milroy disease is inherited in an autosomal dominant manner. Each child of an individual with Milroy disease has a 50% chance of inheriting the mutation. The proportion of cases caused by de novo mutations is not known. Ultrasonography in the third trimester of pregnancy may detect swelling of the dorsum of the feet and more extensive edematous states in an affected fetus. Prenatal testing is possible for pregnancies at increased risk if the disease-causing mutation in the family is known; however, it is rarely requested.

References

PMID: 20301417

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Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
P35916	Activating transcription factor 7 interacting protein	ATF7IP	HPRD	PubMed
P35916	O43915	FIGF	HPRD	PubMed
P35916	P35916	FLT4	HPRD	PubMed
P35916	P62993	GRB2	HPRD	PubMed
P35916	P08648	ITGA5	HPRD	PubMed
P35916	P05556	ITGB1	HPRD	PubMed
P35916	P35968	KDR	HPRD	PubMed
P35916	Q05397	PTK2	HPRD	PubMed
P35916	Q06124	PTPN11	HPRD	PubMed
P35916	P29353	SHC1	HPRD	PubMed
P35916	Q92529	SHC3	HPRD	PubMed
P35916	P49767	VEGFC	HPRD	PubMed
BioGRID:108612	BioGRID:109142	GRB2	BioGRID	PubMed	Reconstituted Complex
BioGRID:108612	BioGRID:114089	IKBKG	BioGRID	PubMed	Reconstituted Complex
BioGRID:108612	BioGRID:109894	ITGB1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:108612	BioGRID:110811	NEDD4	BioGRID	PubMed	Reconstituted Complex
BioGRID:108612	BioGRID:112361	SHC1	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
	NP_005420.1	VEGFC	BIND	PubMed	VEGF-C interacts with VEGFR-3. This interaction was modeled on a demonstrated interaction between human VEGF-C and VEGFR-3 from an unspecified species.
BioGRID:108612	BioGRID:113267	VEGFC	BioGRID	PubMed	Affinity Capture-Western

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General gene information

Markers

RH94055 (e-PCR)
- UniSTS:90113

SHGC-148175 (e-PCR)
- UniSTS:176242

RH80182 (e-PCR)
- UniSTS:87282

D5S2778 (e-PCR)
- UniSTS:473846

Genotypes

See FLT4 SNP Geneview Report
See FLT4 SNP Genotype Report
See FLT4 SNP Variation Viewer Report

Homology

Homologs of the FLT4 gene: The FLT4 gene is conserved in chimpanzee, , dog, cow, mouse, rat, chicken, and zebrafish.
Map Viewer (Mouse, Rat)

Pathways from BioSystems

Cytokine-cytokine receptor interaction, organism-specific biosystem (from KEGG)
Cytokine-cytokine receptor interaction, organism-specific biosystemCytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell ...
Cytokine-cytokine receptor interaction, conserved biosystem (from KEGG)
Cytokine-cytokine receptor interaction, conserved biosystemCytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell ...
Focal adhesion, organism-specific biosystem (from KEGG)
Focal adhesion, organism-specific biosystemCell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the...
Focal adhesion, conserved biosystem (from KEGG)
Focal adhesion, conserved biosystemCell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the...
Signal Transduction, organism-specific biosystem (from REACTOME)
Signal Transduction, organism-specific biosystemSignal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such a...
Signaling by VEGF, organism-specific biosystem (from REACTOME)
Signaling by VEGF, organism-specific biosystemIn normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angioge...
Signaling events mediated by VEGFR1 and VEGFR2, organism-specific biosystem (from Pathway Interaction Database)
Signaling events mediated by VEGFR1 and VEGFR2, organism-specific biosystem
Signaling events mediated by VEGFR1 and VEGFR2
VEGF binds to VEGFR leading to receptor dimerization, organism-specific biosystem (from REACTOME)
VEGF binds to VEGFR leading to receptor dimerization, organism-specific biosystemThe binding of VEGF ligands to VEGFR receptors in the cell membrane induces dimerization and activation of the latter, initiating intracellular signaling cascades that result in proliferation, surviv...
VEGF ligand-receptor interactions, organism-specific biosystem (from REACTOME)
VEGF ligand-receptor interactions, organism-specific biosystemThe VEGF family is encoded by seven genes (VEGF-A, B, C, D, E: PLGF (Placenta Growth Factor)-1, 2). Six isoforms of VEGF-A protein, containing 121, 145, 165, 183, 189, and 206 amino acid residues, an...
VEGFR3 signaling in lymphatic endothelium, organism-specific biosystem (from Pathway Interaction Database)
VEGFR3 signaling in lymphatic endothelium, organism-specific biosystem
VEGFR3 signaling in lymphatic endothelium

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ATP binding	IEA Inferred from Electronic Annotation more info
growth factor binding	IPI Inferred from Physical Interaction more info	PubMed
nucleotide binding	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein phosphatase binding	IPI Inferred from Physical Interaction more info
receptor activity	IEA Inferred from Electronic Annotation more info
transmembrane receptor protein tyrosine kinase activity	IMP Inferred from Mutant Phenotype more info	PubMed
vascular endothelial growth factor-activated receptor activity	IDA Inferred from Direct Assay more info	PubMed
vascular endothelial growth factor-activated receptor activity	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
blood vessel morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
cellular response to vascular endothelial growth factor stimulus	IDA Inferred from Direct Assay more info	PubMed
cellular response to vascular endothelial growth factor stimulus	IMP Inferred from Mutant Phenotype more info	PubMed
lymphangiogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
lymphangiogenesis	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
peptidyl-tyrosine phosphorylation	IDA Inferred from Direct Assay more info	PubMed
positive regulation of ERK1 and ERK2 cascade	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of JNK cascade	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of MAPK cascade	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of cell proliferation	IGI Inferred from Genetic Interaction more info	PubMed
positive regulation of cell proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of endothelial cell migration	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of endothelial cell proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of protein kinase C signaling cascade	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of protein phosphorylation	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation vascular endothelial growth factor production	IMP Inferred from Mutant Phenotype more info	PubMed
protein autophosphorylation	IDA Inferred from Direct Assay more info	PubMed
regulation of blood vessel remodeling	ISS Inferred from Sequence or Structural Similarity more info
sprouting angiogenesis	ISS Inferred from Sequence or Structural Similarity more info
transmembrane receptor protein tyrosine kinase signaling pathway	TAS Traceable Author Statement more info	PubMed
vascular endothelial growth factor receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
vascular endothelial growth factor receptor signaling pathway	IGI Inferred from Genetic Interaction more info	PubMed
vascular endothelial growth factor receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
vascular endothelial growth factor receptor signaling pathway	TAS Traceable Author Statement more info
vascular endothelial growth factor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
vascular endothelial growth factor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
vascular endothelial growth factor signaling pathway	TAS Traceable Author Statement more info	PubMed
vasculature development	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
cytoplasm	IEA Inferred from Electronic Annotation more info
extracellular region	IEA Inferred from Electronic Annotation more info
integral to plasma membrane	IEA Inferred from Electronic Annotation more info
nucleus	IEA Inferred from Electronic Annotation more info
plasma membrane	IDA Inferred from Direct Assay more info	PubMed
plasma membrane	TAS Traceable Author Statement more info

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General protein information

Preferred Names: vascular endothelial growth factor receptor 3

Names: vascular endothelial growth factor receptor 3; FLT-4; VEGFR-3; soluble VEGFR3 variant 1; soluble VEGFR3 variant 2; soluble VEGFR3 variant 3; fms-like tyrosine kinase 4; tyrosine-protein kinase receptor FLT4

NP_002011.2

EC 2.7.10.1

NP_891555.2

EC 2.7.10.1

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_011536.1 RefSeqGene

Range

5001..53119

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_002020.4 → NP_002011.2 vascular endothelial growth factor receptor 3 isoform 2 precursor

Status: REVIEWED

Description

Transcript Variant: This variant (2) contains an alternate 3' terminal exon compared to variant 1. This results in an isoform (2) with a shorter C-terminus compared to isoform 1.

Source sequence(s)

AC122714, AY233382, DB455035, X68203

Consensus CDS

CCDS43412.1

UniProtKB/Swiss-Prot

P35916

Related

ENSP00000377016, OTTHUMP00000223511, ENST00000393347, OTTHUMT00000372538

Conserved Domains (7) summary

cd05102
Location:837 – 1168
Blast Score: 1764

PTKc_VEGFR3; Catalytic domain of the Protein Tyrosine Kinase, Vascular Endothelial Growth Factor Receptor 3

cd00096
Location:695 – 762
Blast Score: 126

Ig; Immunoglobulin domain

cd05862
Location:245 – 329
Blast Score: 403

Ig1_VEGFR; First immunoglobulin (Ig)-like domain of vascular endothelial growth factor (VEGF) receptor(R)

cd05863
Location:352 – 418
Blast Score: 322

Ig2_VEGFR-3; Second immunoglobulin (Ig)-like domain of vascular endothelial growth factor receptor 3 (VEGFR-3)

pfam07679
Location:678 – 765
Blast Score: 160

I-set; Immunoglobulin I-set domain

pfam07714
Location:845 – 1168
Blast Score: 918

Pkinase_Tyr; Protein tyrosine kinase

cl11960
Location:564 – 657
Blast Score: 94

Ig; Immunoglobulin domain
NM_182925.4 → NP_891555.2 vascular endothelial growth factor receptor 3 isoform 1 precursor

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longer isoform (1).

Source sequence(s)

AC122714, AY233383, DB455035, X68203

Consensus CDS

CCDS4457.1

UniProtKB/Swiss-Prot

P35916

Related

ENSP00000261937, OTTHUMP00000161539, ENST00000261937, OTTHUMT00000253527

Conserved Domains (7) summary

cd05102
Location:837 – 1168
Blast Score: 1765

PTKc_VEGFR3; Catalytic domain of the Protein Tyrosine Kinase, Vascular Endothelial Growth Factor Receptor 3

cd00096
Location:695 – 762
Blast Score: 125

Ig; Immunoglobulin domain

cd05862
Location:245 – 329
Blast Score: 403

Ig1_VEGFR; First immunoglobulin (Ig)-like domain of vascular endothelial growth factor (VEGF) receptor(R)

cd05863
Location:352 – 418
Blast Score: 323

Ig2_VEGFR-3; Second immunoglobulin (Ig)-like domain of vascular endothelial growth factor receptor 3 (VEGFR-3)

pfam07679
Location:678 – 765
Blast Score: 160

I-set; Immunoglobulin I-set domain

pfam07714
Location:845 – 1168
Blast Score: 920

Pkinase_Tyr; Protein tyrosine kinase

cl11960
Location:564 – 657
Blast Score: 94

Ig; Immunoglobulin domain

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000005.9 Reference GRCh37.p5 Primary Assembly

Range

180028506..180076624, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000137.1 Alternate HuRef

Range

174752484..174782989, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AC122714.2 (75679..139039)	None
genomic	CH471165.2	EAW53749.1
		EAW53750.1
genomic	CS067238.1	CAI84582.1
genomic	CS172288.1	CAJ32888.1
genomic	CS172403.1	CAJ33671.1
genomic	CS172817.1	CAJ33685.1
genomic	CS172819.1	CAJ32905.1
genomic	HC040608.1	CBH30507.1
genomic	HC040723.1	CBH30547.1
mRNA	AB209637.1	BAD92874.1
mRNA	AK291679.1	BAF84368.1
mRNA	AK309910.1	None
mRNA	AY233382.1	AAO89504.1
mRNA	AY233383.1	AAO89505.1
mRNA	BC027302.1	None
mRNA	CA438330.1	None
mRNA	DB455035.2	None
mRNA	EU826564.1	ACF47600.1
mRNA	EU826565.1	ACF47601.1
mRNA	EU826566.1	ACF47602.1
mRNA	S66407.1	AAB28539.1
mRNA	U43143.1	AAA85215.1
mRNA	X68203.1	CAA48290.1
mRNA	X69878.1	CAA49505.1
other-genetic	BC167816.1	AAI67816.1