Reviewed, UniProtKB/Swiss-Prot P35916 (VGFR3_HUMAN)

Names and origin

Protein names

Recommended name:
    Vascular endothelial growth factor receptor 3
      Short name=VEGFR-3
    EC=2.7.10.1
Alternative name(s):
    Tyrosine-protein kinase receptor FLT4

Gene names

Name:

FLT4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1298 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor for VEGFC. Has a tyrosine-protein kinase activity.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Placenta, lung, heart, and kidney, does not seem to be expressed in pancreas and brain.
Involvement in disease	Defects in FLT4 are the cause of lymphedema hereditary type 1 (LYH1A) [MIM:153100]; also known as Nonne-Milroy lymphedema or Milroy disease. Hereditary lymphedema is a chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. Ref.10 Ref.11 Ref.12 Defects in FLT4 are found in juvenile hemangioma. Juvenile hemangiomas are the most common tumors of infancy, occurring as many as 10% of all births. These benign vascular lesions enlarge rapidly during the first year of life by hyperplasia of endothelial cells and attendant pericytes, and then spontaneously involute over a period of years, leaving loose fibrofatty tissue.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 7 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Immunoglobulin domain Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	positive regulation of cell proliferation Inferred from genetic interaction. Source: MGI protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro vascular endothelial growth factor receptor signaling pathway Inferred from direct assay. Source: MGI
Cellular component	integral to plasma membrane Ref.4 Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct vascular endothelial growth factor receptor activity Ref.12 Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
KDR	P35968	1	EBI-1005467,EBI-1005487

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Ref.7
	Chain	25 – 1298	1274	Vascular endothelial growth factor receptor 3		PRO_0000016776
Regions
	Topological domain	25 – 775	751	Extracellular Potential
	Transmembrane	776 – 797	22	Potential
	Topological domain	798 – 1298	501	Cytoplasmic Potential
	Domain	30 – 127	98	Ig-like C2-type 1
	Domain	151 – 213	63	Ig-like C2-type 2
	Domain	219 – 326	108	Ig-like C2-type 3
	Domain	331 – 415	85	Ig-like C2-type 4
	Domain	422 – 552	131	Ig-like C2-type 5
	Domain	555 – 671	117	Ig-like C2-type 6
	Domain	678 – 764	87	Ig-like C2-type 7
	Domain	845 – 1173	329	Protein kinase
	Nucleotide binding	851 – 859	9	ATP By similarity
Sites
	Active site	1037	1	Proton acceptor By similarity
	Binding site	879	1	ATP By similarity
Amino acid modifications
	Modified residue	1063	1	Phosphotyrosine Ref.9
	Modified residue	1068	1	Phosphotyrosine; by autocatalysis By similarity
	Glycosylation	33	1	N-linked (GlcNAc...) Potential
	Glycosylation	104	1	N-linked (GlcNAc...) Potential
	Glycosylation	166	1	N-linked (GlcNAc...) Potential
	Glycosylation	251	1	N-linked (GlcNAc...) Potential
	Glycosylation	299	1	N-linked (GlcNAc...) Potential
	Glycosylation	411	1	N-linked (GlcNAc...) Potential
	Glycosylation	515	1	N-linked (GlcNAc...) Potential
	Glycosylation	527	1	N-linked (GlcNAc...) Ref.8
	Glycosylation	594	1	N-linked (GlcNAc...) Potential
	Glycosylation	683	1	N-linked (GlcNAc...) Potential
	Glycosylation	690	1	N-linked (GlcNAc...) Potential
	Glycosylation	758	1	N-linked (GlcNAc...) Potential
	Disulfide bond	51 ↔ 111		Potential
	Disulfide bond	158 ↔ 206		Potential
	Disulfide bond	252 ↔ 310		Potential
	Disulfide bond	445 ↔ 534		Potential
	Disulfide bond	578 ↔ 653		Potential
	Disulfide bond	699 ↔ 751		Potential
Natural variations
	Natural variant	149	1	N → D Ref.14		VAR_042062
	Natural variant	378	1	R → C in a renal clear cell carcinoma sample; somatic mutation. Ref.14		VAR_042063
	Natural variant	494	1	T → A: dbSNP rs307826. Ref.14 Ref.13		VAR_018407
	Natural variant	527	1	N → S: dbSNP rs35874891. Ref.14		VAR_034379
	Natural variant	641	1	P → S Does not affect kinase activity. Ref.12 Ref.14		VAR_018408
	Natural variant	857	1	G → R in LYH1A; loss of kinase activity. Ref.12		VAR_018409
	Natural variant	868	1	H → Y Ref.14		VAR_042064
	Natural variant	890	1	H → Q: dbSNP rs448012. Ref.13 Ref.4		VAR_018410
	Natural variant	954	1	P → S in juvenile hemangioma. Ref.13		VAR_018411
	Natural variant	1010	1	T → I in a metastatic melanoma sample; somatic mutation. Ref.14		VAR_042065
	Natural variant	1031	1	R → Q Ref.14		VAR_042066
	Natural variant	1035	1	H → R in LYH1A; loss of kinase activity. Ref.11		VAR_018412
	Natural variant	1041	1	R → P in LYH1A; loss of kinase activity. Ref.12		VAR_018413
	Natural variant	1044	1	L → P in LYH1A; loss of kinase activity. Ref.12		VAR_018414
	Natural variant	1049	1	D → N Ref.14		VAR_042067
	Natural variant	1075	1	R → Q Ref.14		VAR_042068
	Natural variant	1114	1	P → L in LYH1A; loss of kinase activity. Ref.10 Ref.12		VAR_018415
	Natural variant	1137	1	P → S in juvenile hemangioma. Ref.13		VAR_018416
	Natural variant	1146	1	R → H Ref.14 Ref.13 Ref.4		VAR_018417
Experimental info
	Sequence conflict	24	1	G → D in CAA49505. Ref.4
	Sequence conflict	745	1	R → P in CAA49505. Ref.4
	Sequence conflict	752 – 753	2	NA → RP in CAA49505. Ref.4
	Sequence conflict	1128	1	L → V in CAA49505. Ref.4
	Sequence conflict	1164	1	E → D in CAA49505. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	P35916-1 [UniParc]. Last modified October 1, 1996. Version 2. Checksum: 3DC469ED3CB8B3B1	FASTA	1,298	145,599
	10 20 30 40 50 60 MQRGAALCLR LWLCLGLLDG LVSGYSMTPP TLNITEESHV IDTGDSLSIS CRGQHPLEWA 70 80 90 100 110 120 WPGAQEAPAT GDKDSEDTGV VRDCEGTDAR PYCKVLLLHE VHANDTGSYV CYYKYIKARI 130 140 150 160 170 180 EGTTAASSYV FVRDFEQPFI NKPDTLLVNR KDAMWVPCLV SIPGLNVTLR SQSSVLWPDG 190 200 210 220 230 240 QEVVWDDRRG MLVSTPLLHD ALYLQCETTW GDQDFLSNPF LVHITGNELY DIQLLPRKSL 250 260 270 280 290 300 ELLVGEKLVL NCTVWAEFNS GVTFDWDYPG KQAERGKWVP ERRSQQTHTE LSSILTIHNV 310 320 330 340 350 360 SQHDLGSYVC KANNGIQRFR ESTEVIVHEN PFISVEWLKG PILEATAGDE LVKLPVKLAA 370 380 390 400 410 420 YPPPEFQWYK DGKALSGRHS PHALVLKEVT EASTGTYTLA LWNSAAGLRR NISLELVVNV 430 440 450 460 470 480 PPQIHEKEAS SPSIYSRHSR QALTCTAYGV PLPLSIQWHW RPWTPCKMFA QRSLRRRQQQ 490 500 510 520 530 540 DLMPQCRDWR AVTTQDAVNP IESLDTWTEF VEGKNKTVSK LVIQNANVSA MYKCVVSNKV 550 560 570 580 590 600 GQDERLIYFY VTTIPDGFTI ESKPSEELLE GQPVLLSCQA DSYKYEHLRW YRLNLSTLHD 610 620 630 640 650 660 AHGNPLLLDC KNVHLFATPL AASLEEVAPG ARHATLSLSI PRVAPEHEGH YVCEVQDRRS 670 680 690 700 710 720 HDKHCHKKYL SVQALEAPRL TQNLTDLLVN VSDSLEMQCL VAGAHAPSIV WYKDERLLEE 730 740 750 760 770 780 KSGVDLADSN QKLSIQRVRE EDAGRYLCSV CNAKGCVNSS ASVAVEGSED KGSMEIVILV 790 800 810 820 830 840 GTGVIAVFFW VLLLLIFCNM RRPAHADIKT GYLSIIMDPG EVPLEEQCEY LSYDASQWEF 850 860 870 880 890 900 PRERLHLGRV LGYGAFGKVV EASAFGIHKG SSCDTVAVKM LKEGATASEH RALMSELKIL 910 920 930 940 950 960 IHIGNHLNVV NLLGACTKPQ GPLMVIVEFC KYGNLSNFLR AKRDAFSPCA EKSPEQRGRF 970 980 990 1000 1010 1020 RAMVELARLD RRRPGSSDRV LFARFSKTEG GARRASPDQE AEDLWLSPLT MEDLVCYSFQ 1030 1040 1050 1060 1070 1080 VARGMEFLAS RKCIHRDLAA RNILLSESDV VKICDFGLAR DIYKDPDYVR KGSARLPLKW 1090 1100 1110 1120 1130 1140 MAPESIFDKV YTTQSDVWSF GVLLWEIFSL GASPYPGVQI NEEFCQRLRD GTRMRAPELA 1150 1160 1170 1180 1190 1200 TPAIRRIMLN CWSGDPKARP AFSELVEILG DLLQGRGLQE EEEVCMAPRS SQSSEEGSFS 1210 1220 1230 1240 1250 1260 QVSTMALHIA QADAEDSPPS LQRHSLAARY YNWVSFPGCL ARGAETRGSS RMKTFEEFPM 1270 1280 1290 TPTTYKGSVD NQTDSGMVLA SEEFEQIESR HRQESGFR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines." Pajusola K., Aprelikova O., Korhonen J., Kaipainen A., Pertovaara L., Alitalo R., Alitalo K. Cancer Res. 52:5738-5743(1992) [PubMed: 1327515] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	Erratum Pajusola K., Aprelikova O., Korhonen J., Kaipainen A., Pertovaara L., Alitalo R., Alitalo K. Cancer Res. 53:3845-3845(1993)
[3]	"Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene." Galland F., Karamysheva A., Mattei M.-G., Rosnet O., Marchetto S., Birnbaum D. Genomics 13:475-478(1992) [PubMed: 1319394] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor." Galland F., Karamysheva A., Pebusque M.-J., Borg J.-P., Rottapel R., Dubreuil P., Rosnet O., Birnbaum D. Oncogene 8:1233-1240(1993) [PubMed: 8386825] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS GLN-890 AND HIS-1146. Tissue: Placenta.
[5]	"Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4." Lee J., Gray A., Yuan J., Luoh S.-M., Avraham H., Wood W.I. Proc. Natl. Acad. Sci. U.S.A. 93:1988-1992(1996) [PubMed: 8700872] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter." Aprelikova O., Pajusola K., Partanen J., Armstrong E., Alitalo R., Bailey S.K., McMahon J., Wasmuth J., Huebner K., Alitalo K. Cancer Res. 52:746-748(1992) [PubMed: 1310071] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 761-1190.
[7]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-39.
[8]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-527, MASS SPECTROMETRY. Tissue: Plasma.
[9]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1063 AND TYR-1068, MASS SPECTROMETRY.
[10]	"Hereditary lymphedema: evidence for linkage and genetic heterogeneity." Ferrell R.E., Levinson K.L., Esman J.H., Kimak M.A., Lawrence E.C., Barmada M.M., Finegold D.N. Hum. Mol. Genet. 7:2073-2078(1998) [PubMed: 9817924] [Abstract] Cited for: VARIANT LYH1A LEU-1114.
[11]	"Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase." Irrthum A., Karkkainen M.J., Devriendt K., Alitalo K., Vikkula M. Am. J. Hum. Genet. 67:295-301(2000) [PubMed: 10856194] [Abstract] Cited for: INVOLVEMENT IN LYH1A, CHARACTERIZATION OF VARIANT LYH1A ARG-1035.
[12]	"Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema." Karkkainen M.J., Ferrell R.E., Lawrence E.C., Kimak M.A., Levinson K.L., McTigue M.A., Alitalo K., Finegold D.N. Nat. Genet. 25:153-159(2000) [PubMed: 10835628] [Abstract] Cited for: VARIANTS LYH1A ARG-857; PRO-1041; PRO-1044 AND LEU-1114, VARIANT SER-641, CHARACTERIZATION OF VARIANTS.
[13]	"Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma." Walter J.W., North P.E., Waner M., Mizeracki A., Blei F., Walker J.W.T., Reinisch J.F., Marchuk D.A. Genes Chromosomes Cancer 33:295-303(2002) [PubMed: 11807987] [Abstract] Cited for: VARIANTS JUVENILE HEMANGIOMA SER-954 AND SER-1137, VARIANTS ALA-494; GLN-890 AND HIS-1146.
[14]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASP-149; CYS-378; ALA-494; SER-527; SER-641; TYR-868; ILE-1010; GLN-1031; ASN-1049; GLN-1075 AND HIS-1146.
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

FLT4 entry

Cross-references

Sequence databases
EMBLGenBankDDBJ	X69878 mRNA. Translation: CAA49505.1. U43143 mRNA. Translation: AAA85215.1. X68203 mRNA. Translation: CAA48290.1. Different initiation.
IPI	IPI00337568.
PIR	A48999.
RefSeq	NP_002011.2.
UniGene	Hs.646917
3D structure databases
HSSP	HSSP built from PDB template 1VR2 based on UniProtKB P35968.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:5739N.
IntAct	P35916. 1 interaction.
PTM databases
PhosphoSite	P35916.
Proteomic databases
PRIDE	P35916.
Genome annotation databases
Ensembl	ENSG00000037280. Homo sapiens. [Contig view]
GeneID	2324.
KEGG	hsa:2324.
Organism-specific databases
GeneCards	GC05M179962.
H-InvDB	HIX0032025.
HGNC	HGNC:3767. FLT4.
HPA	CAB000099.
MIM	136352. gene. 153100. phenotype.
Orphanet	2416. Lymphedema, congenital.
PharmGKB	PA28183.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	P35916.
Enzyme and pathway databases
BRENDA	2.7.10.1. 247.
Pathway_Interaction_DB	vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2. lymphangiogenesis_pathway. VEGFR3 signaling in lymphatic endothelium.
Reactome	REACT_12529. Signaling by VEGF.
Gene expression databases
ArrayExpress	P35916.
Bgee	P35916.
CleanEx	HS_FLT4.
GermOnline	ENSG00000037280. Homo sapiens.
Family and domain databases
InterPro	IPR013151. Ig. IPR007110. Ig-like. IPR013783. Ig-like_fold. IPR013098. Ig_I-set. IPR003599. Ig_sub. IPR003598. Ig_sub2. IPR013106. Ig_V-set. IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_BS. IPR001824. Recept_tyr_kinase-III_CS. IPR001245. Tyr_pkinase. IPR008266. Tyr_pkinase_AS. IPR009137. VEGFR3_N. IPR009134. VEGFR_N. [Graphical view]
Gene3D	G3DSA:2.60.40.10. Ig-like_fold. 4 hits.
Pfam	PF07679. I-set. 1 hit. PF00047. ig. 1 hit. PF07714. Pkinase_Tyr. 1 hit. PF07686. V-set. 1 hit. [Graphical view]
PRINTS	PR01832. VEGFRECEPTOR. PR01835. VEGFRECEPTR3.
ProDom	PD000001. Prot_kinase. 2 hits. [Graphical view] [Entries sharing at least one domain]
SMART	SM00409. IG. 4 hits. SM00408. IGc2. 2 hits. SM00219. TyrKc. 1 hit. [Graphical view]
PROSITE	PS50835. IG_LIKE. 6 hits. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS00240. RECEPTOR_TYR_KIN_III. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB00398. Sorafenib. DB01268. Sunitinib.
NextBio	9433.
SOURCE	Search...

Entry information

Entry name

VGFR3_HUMAN

Accession

Primary (citable) accession number: P35916

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	October 1, 1996
Last modified:	June 16, 2009
This is version 110 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)