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P35917 (VGFR3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 147. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Vascular endothelial growth factor receptor 3

Short name=VEGFR-3
EC=2.7.10.1
Alternative name(s):
Fms-like tyrosine kinase 4
Short name=FLT-4
Tyrosine-protein kinase receptor FLT4
Gene names
Name:Flt4
Synonyms:Flt-4, Vegfr3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1363 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'. Ref.3 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Enzyme regulation

Present in an inactive conformation in the absence of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues By similarity.

Subunit structure

Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex with SRC and ITGB1 By similarity.

Subcellular location

Cell membrane; Single-pass type I membrane protein. Cytoplasm. Nucleus By similarity. Note: Ligand-mediated autophosphorylation leads to rapid internalization. Ref.7

Tissue specificity

Expressed in adult lung and liver, and in fetal liver, brain, intestine and placenta. Ref.5

Domain

The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding By similarity.

Post-translational modification

Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H2O2 is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC By similarity.

Disruption phenotype

Embryonic lethality at about 13 dpc, due to failure of remodeling of the yolk sac capillary network and defects in remodeling and maturation of primary vascular networks. Ref.3

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
   Biological processAngiogenesis
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   DomainImmunoglobulin domain
Repeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processblood vessel morphogenesis

Inferred from mutant phenotype Ref.3. Source: UniProtKB

lymph vessel development

Inferred from mutant phenotype PubMed 19903896. Source: BHF-UCL

lymphangiogenesis

Inferred from mutant phenotype Ref.6. Source: UniProtKB

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of ERK1 and ERK2 cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell proliferation

Inferred from genetic interaction PubMed 9247316. Source: MGI

positive regulation of endothelial cell migration

Inferred from electronic annotation. Source: Ensembl

positive regulation of endothelial cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein kinase C signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation vascular endothelial growth factor production

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Inferred from electronic annotation. Source: Ensembl

regulation of blood vessel remodeling

Inferred from mutant phenotype Ref.3. Source: UniProtKB

sprouting angiogenesis

Inferred from mutant phenotype Ref.5. Source: UniProtKB

vascular endothelial growth factor receptor signaling pathway

Inferred from electronic annotation. Source: InterPro

vascular endothelial growth factor signaling pathway

Inferred from genetic interaction PubMed 9247316. Source: GOC

vasculature development

Inferred from mutant phenotype Ref.3. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of plasma membrane

Inferred from electronic annotation. Source: InterPro

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

receptor complex

Inferred from sequence orthology PubMed 23382219. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 20224550. Source: IntAct

vascular endothelial growth factor-activated receptor activity

Inferred from genetic interaction PubMed 9247316. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

KdrP359182EBI-7845747,EBI-1555005

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2424 Potential
Chain25 – 13631339Vascular endothelial growth factor receptor 3
PRO_0000016777

Regions

Topological domain25 – 775751Extracellular Potential
Transmembrane776 – 79621Helical; Potential
Topological domain797 – 1363567Cytoplasmic Potential
Domain44 – 11875Ig-like C2-type 1
Domain151 – 21363Ig-like C2-type 2
Domain230 – 32697Ig-like C2-type 3
Domain331 – 41585Ig-like C2-type 4
Domain422 – 552131Ig-like C2-type 5
Domain555 – 671117Ig-like C2-type 6
Domain678 – 76487Ig-like C2-type 7
Domain845 – 1173329Protein kinase
Nucleotide binding851 – 8599ATP By similarity

Sites

Active site10371Proton acceptor By similarity
Binding site8791ATP By similarity

Amino acid modifications

Modified residue8301Phosphotyrosine; by SRC By similarity
Modified residue8331Phosphotyrosine; by SRC By similarity
Modified residue10631Phosphotyrosine; by autocatalysis and SRC By similarity
Modified residue10681Phosphotyrosine; by autocatalysis By similarity
Modified residue12301Phosphotyrosine; by autocatalysis By similarity
Modified residue12311Phosphotyrosine; by autocatalysis By similarity
Modified residue12651Phosphotyrosine; by autocatalysis By similarity
Modified residue13331Phosphotyrosine; by autocatalysis and SRC By similarity
Modified residue13371Phosphotyrosine; by autocatalysis and SRC By similarity
Modified residue13631Phosphotyrosine; by autocatalysis By similarity
Glycosylation331N-linked (GlcNAc...) Potential
Glycosylation1041N-linked (GlcNAc...) Potential
Glycosylation1661N-linked (GlcNAc...) Potential
Glycosylation2511N-linked (GlcNAc...) Potential
Glycosylation2991N-linked (GlcNAc...) Potential
Glycosylation4111N-linked (GlcNAc...) Potential
Glycosylation5151N-linked (GlcNAc...) Potential
Glycosylation5271N-linked (GlcNAc...) Potential
Glycosylation5821N-linked (GlcNAc...) Ref.4
Glycosylation5941N-linked (GlcNAc...) Potential
Glycosylation6831N-linked (GlcNAc...) Potential
Glycosylation6901N-linked (GlcNAc...) Potential
Glycosylation7581N-linked (GlcNAc...) Potential
Disulfide bond51 ↔ 111 By similarity
Disulfide bond158 ↔ 206 By similarity
Disulfide bond252 ↔ 310 By similarity
Disulfide bond445 ↔ 534 By similarity
Disulfide bond578 ↔ 653 By similarity
Disulfide bond699 ↔ 751 By similarity

Sequences

Sequence LengthMass (Da)Tools
P35917 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: F1BF8A2BDEF99BE9

FASTA1,363153,016
        10         20         30         40         50         60 
MQPGAALNLR LWLCLGLLQG LANGYSMTPP TLNITEDSYV IDTGDSLSIS CRGQHPLEWT 

        70         80         90        100        110        120 
WPGAQEVLTT GGKDSEDTRV VHDCEGTEAR PYCKVLLLAQ THANNTGSYH CYYKYIKARI 

       130        140        150        160        170        180 
EGTTAASTYV FVRDFKHPFI NKPDTLLVNR KDSMWVPCLV SIPGLNITLR SQSSALHPDG 

       190        200        210        220        230        240 
QEVLWDDRRG MRVPTQLLRD ALYLQCETTW GDQNFLSNLF VVHITGNELY DIQLYPKKSM 

       250        260        270        280        290        300 
ELLVGEKLVL NCTVWAEFDS GVTFDWDYPG KQAERAKWVP ERRSQQTHTE LSSILTIHNV 

       310        320        330        340        350        360 
SQNDLGPYVC EANNGIQRFR ESTEVIVHEK PFISVEWLKG PVLEATAGDE LVKLPVKLAA 

       370        380        390        400        410        420 
YPPPEFQWYK DRKAVTGRHN PHALVLKEVT EASAGVYTLA LWNSAAGLRQ NISLELVVNV 

       430        440        450        460        470        480 
PPHIHEKEAS SPSIYSRHSR QTLTCTAYGV PQPLSVQWHW RPWTPCKTFA QRSLRRRQQR 

       490        500        510        520        530        540 
DGMPQCRDWK EVTTQDAVNP IESLDSWTEF VEGKNKTVSK LVIQDANVSA MYKCVVVNKV 

       550        560        570        580        590        600 
GQDERLIYFY VTTIPDGFSI ESEPSEDPLE GQSVRLSCRA DNYTYEHLRW YRLNLSTLHD 

       610        620        630        640        650        660 
AQGNPLLLDC KNVHLFATPL EANLEEAEPG ARHATLSLNI PRVAPEDEGD YVCEVQDRRS 

       670        680        690        700        710        720 
QDKHCHKKYL SVQALEAPRL TQNLTDLLVN VSDSLEMRCP VAGAHVPSIV WYKDERLLEK 

       730        740        750        760        770        780 
ESGIDLADSN QRLSIQRVRE EDAGRYLCSV CNAKGCVNSS ASVAVEGSED KGSMEIVILI 

       790        800        810        820        830        840 
GTGVIAVFFW VLLLLIFCNM KRPAHADIKT GYLSIIMDPG EVPLEEQCEY LSYDASQWEF 

       850        860        870        880        890        900 
PRERLHLGRV LGHGAFGKVV EASAFGINKG SSCDTVAVKM LKEGATASEH RALMSELKIL 

       910        920        930        940        950        960 
IHIGNHLNVV NLLGACTKPN GPLMVIVEFC KYGNLSNFLR VKRDTFNPYA EKSPEQRRRF 

       970        980        990       1000       1010       1020 
RAMVEGAKAD RRRPGSSDRA LFTRFLMGKG SARRAPLVQE AEDLWLSPLT MEDLVCYSFQ 

      1030       1040       1050       1060       1070       1080 
VARGMEFLAS RKCIHRDLAA RNILLSESDI VKICDFGLAR DIYKDPDYVR KGSARLPLKW 

      1090       1100       1110       1120       1130       1140 
MAPESIFDKV YTTQSDVWSF GVLLWEIFSL GASPYPGVQI NEEFCQRLKD GTRMRAPELA 

      1150       1160       1170       1180       1190       1200 
TPAIRHIMQS CWSGDPKARP AFSDLVEILG DLLQGGGWQE EEEERMALHS SQSSEEDGFM 

      1210       1220       1230       1240       1250       1260 
QASTTALHIT EADADDSPPS MHCHSLAARY YNCVSFPGRL ARGTKTPGSS RMKTFEELPM 

      1270       1280       1290       1300       1310       1320 
TPTTYKASMD NQTDSGMVLA SEEFEELESR HRPEGSFSCK GPGQHMDIPR GHPDPQGRRR 

      1330       1340       1350       1360 
RPTQGAQGGK VFYNNEYGEV SQPCTEGDCC PSAGSTFFAD SSY 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning of murine FLT and FLT4."
Finnerty H., Kelleher K., Morris G.E., Bean K., Merberg D.M., Kriz R., Morris J.C., Sookdeo H., Turner K.J., Wood C.R.
Oncogene 8:2293-2298(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6J.
[2]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1033-1072.
[3]"Cardiovascular failure in mouse embryos deficient in VEGF receptor-3."
Dumont D.J., Jussila L., Taipale J., Lymboussaki A., Mustonen T., Pajusola K., Breitman M., Alitalo K.
Science 282:946-949(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[4]"Proteome-wide characterization of N-glycosylation events by diagonal chromatography."
Ghesquiere B., Van Damme J., Martens L., Vandekerckhove J., Gevaert K.
J. Proteome Res. 5:2438-2447(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-582.
Strain: C57BL/6.
Tissue: Plasma.
[5]"Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation."
Tammela T., Zarkada G., Wallgard E., Murtomaki A., Suchting S., Wirzenius M., Waltari M., Hellstrom M., Schomber T., Peltonen R., Freitas C., Duarte A., Isoniemi H., Laakkonen P., Christofori G., Yla-Herttuala S., Shibuya M., Pytowski B. expand/collapse author list , Eichmann A., Betsholtz C., Alitalo K.
Nature 454:656-660(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[6]"VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis."
Zhang L., Zhou F., Han W., Shen B., Luo J., Shibuya M., He Y.
Cell Res. 20:1319-1331(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN LYMPHANGIOGENESIS.
[7]"Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis."
Wang Y., Nakayama M., Pitulescu M.E., Schmidt T.S., Bochenek M.L., Sakakibara A., Adams S., Davy A., Deutsch U., Luthi U., Barberis A., Benjamin L.E., Makinen T., Nobes C.D., Adams R.H.
Nature 465:483-486(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS, SUBCELLULAR LOCATION.
[8]"Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer."
Yang H., Kim C., Kim M.J., Schwendener R.A., Alitalo K., Heston W., Kim I., Kim W.J., Koh G.Y.
Mol. Cancer 10:36-36(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN LYMPHANGIOGENESIS, ROLE IN CANCER.
[9]"VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling."
Tammela T., Zarkada G., Nurmi H., Jakobsson L., Heinolainen K., Tvorogov D., Zheng W., Franco C.A., Murtomaki A., Aranda E., Miura N., Yla-Herttuala S., Fruttiger M., Makinen T., Eichmann A., Pollard J.W., Gerhardt H., Alitalo K.
Nat. Cell Biol. 13:1202-1213(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L07296 mRNA. Translation: AAA40077.1.
CCDSCCDS24618.1.
PIRI58375.
RefSeqNP_032055.1. NM_008029.3.
UniGeneMm.3291.

3D structure databases

ProteinModelPortalP35917.
SMRP35917. Positions 27-765, 821-1223.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid199709. 3 interactions.
DIPDIP-60714N.
IntActP35917. 1 interaction.
MINTMINT-5313593.
STRING10090.ENSMUSP00000020617.

Chemistry

BindingDBP35917.

PTM databases

PhosphoSiteP35917.

Proteomic databases

PaxDbP35917.
PRIDEP35917.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000020617; ENSMUSP00000020617; ENSMUSG00000020357.
GeneID14257.
KEGGmmu:14257.
UCSCuc007iqu.2. mouse.

Organism-specific databases

CTD2324.
MGIMGI:95561. Flt4.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000037949.
HOVERGENHBG053432.
InParanoidP35917.
KOK05097.
OMAPAHADIK.
OrthoDBEOG75F4CC.
PhylomeDBP35917.
TreeFamTF325768.

Enzyme and pathway databases

BRENDA2.7.10.1. 3474.

Gene expression databases

ArrayExpressP35917.
BgeeP35917.
CleanExMM_FLT4.
GenevestigatorP35917.

Family and domain databases

Gene3D2.60.40.10. 9 hits.
InterProIPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR001824. Tyr_kinase_rcpt_3_CS.
IPR009137. VEGFR3_rcpt.
[Graphical view]
PANTHERPTHR24416:SF49. PTHR24416:SF49. 1 hit.
PfamPF07679. I-set. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSPR01835. VEGFRECEPTR3.
SMARTSM00409. IG. 4 hits.
SM00408. IGc2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 2 hits.
PROSITEPS50835. IG_LIKE. 5 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]
ProtoNetSearch...

Other

NextBio285591.
PROP35917.
SOURCESearch...

Entry information

Entry nameVGFR3_MOUSE
AccessionPrimary (citable) accession number: P35917
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: July 9, 2014
This is version 147 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot