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Protein

Vascular endothelial growth factor receptor 3

Gene

Flt4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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'.6 Publications

Catalytic activityi

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

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei879ATPPROSITE-ProRule annotation1
Active sitei1037Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi851 – 859ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • blood vessel morphogenesis Source: UniProtKB
  • cellular response to vascular endothelial growth factor stimulus Source: MGI
  • lung alveolus development Source: MGI
  • lymphangiogenesis Source: UniProtKB
  • lymph vessel development Source: BHF-UCL
  • negative regulation of apoptotic process Source: MGI
  • peptidyl-tyrosine phosphorylation Source: MGI
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of endothelial cell migration Source: MGI
  • positive regulation of endothelial cell proliferation Source: MGI
  • positive regulation of ERK1 and ERK2 cascade Source: MGI
  • positive regulation of JNK cascade Source: MGI
  • positive regulation of MAPK cascade Source: MGI
  • positive regulation of protein kinase C signaling Source: MGI
  • positive regulation of protein phosphorylation Source: MGI
  • positive regulation of vascular endothelial growth factor production Source: MGI
  • protein autophosphorylation Source: MGI
  • regulation of blood vessel remodeling Source: UniProtKB
  • respiratory gaseous exchange Source: MGI
  • respiratory system process Source: MGI
  • sprouting angiogenesis Source: UniProtKB
  • vascular endothelial growth factor receptor signaling pathway Source: MGI
  • vasculature development Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Angiogenesis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.
ReactomeiR-MMU-195399. VEGF binds to VEGFR leading to receptor dimerization.

Names & Taxonomyi

Protein namesi
Recommended name:
Vascular endothelial growth factor receptor 3 (EC:2.7.10.1)
Short name:
VEGFR-3
Alternative name(s):
Fms-like tyrosine kinase 4
Short name:
FLT-4
Tyrosine-protein kinase receptor FLT4
Gene namesi
Name:Flt4
Synonyms:Flt-4, Vegfr3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:95561. Flt4.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini25 – 775ExtracellularSequence analysisAdd BLAST751
Transmembranei776 – 796HelicalSequence analysisAdd BLAST21
Topological domaini797 – 1363CytoplasmicSequence analysisAdd BLAST567

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

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.1 Publication

Chemistry databases

GuidetoPHARMACOLOGYi1814.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
ChainiPRO_000001677725 – 1363Vascular endothelial growth factor receptor 3Add BLAST1339

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi33N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi51 ↔ 111PROSITE-ProRule annotation
Glycosylationi104N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi158 ↔ 206PROSITE-ProRule annotation
Glycosylationi166N-linked (GlcNAc...)Sequence analysis1
Glycosylationi251N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi252 ↔ 310PROSITE-ProRule annotation
Glycosylationi299N-linked (GlcNAc...)Sequence analysis1
Glycosylationi411N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi445 ↔ 534PROSITE-ProRule annotation
Glycosylationi515N-linked (GlcNAc...)Sequence analysis1
Glycosylationi527N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi578 ↔ 653PROSITE-ProRule annotation
Glycosylationi582N-linked (GlcNAc...)1 Publication1
Glycosylationi594N-linked (GlcNAc...)Sequence analysis1
Glycosylationi683N-linked (GlcNAc...)Sequence analysis1
Glycosylationi690N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi699 ↔ 751PROSITE-ProRule annotation
Glycosylationi758N-linked (GlcNAc...)Sequence analysis1
Modified residuei830Phosphotyrosine; by SRCBy similarity1
Modified residuei833Phosphotyrosine; by SRCBy similarity1
Modified residuei1063Phosphotyrosine; by autocatalysis and SRCBy similarity1
Modified residuei1068Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1230Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1231Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1265Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1333Phosphotyrosine; by autocatalysis and SRCBy similarity1
Modified residuei1337Phosphotyrosine; by autocatalysis and SRCBy similarity1
Modified residuei1363Phosphotyrosine; by autocatalysisBy similarity1

Post-translational modificationi

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).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiP35917.
PeptideAtlasiP35917.
PRIDEiP35917.

PTM databases

iPTMnetiP35917.
PhosphoSitePlusiP35917.

Expressioni

Tissue specificityi

Expressed in adult lung and liver, and in fetal liver, brain, intestine and placenta.1 Publication

Gene expression databases

BgeeiENSMUSG00000020357.
CleanExiMM_FLT4.
ExpressionAtlasiP35917. baseline and differential.
GenevisibleiP35917. MM.

Interactioni

Subunit structurei

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).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
KdrP359182EBI-7845747,EBI-1555005

GO - Molecular functioni

Protein-protein interaction databases

BioGridi199709. 5 interactors.
DIPiDIP-60714N.
IntActiP35917. 1 interactor.
MINTiMINT-5313593.
STRINGi10090.ENSMUSP00000020617.

Chemistry databases

BindingDBiP35917.

Structurei

3D structure databases

ProteinModelPortaliP35917.
SMRiP35917.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini44 – 118Ig-like C2-type 1Add BLAST75
Domaini151 – 213Ig-like C2-type 2Add BLAST63
Domaini230 – 326Ig-like C2-type 3Add BLAST97
Domaini331 – 415Ig-like C2-type 4Add BLAST85
Domaini422 – 552Ig-like C2-type 5Add BLAST131
Domaini555 – 671Ig-like C2-type 6Add BLAST117
Domaini678 – 764Ig-like C2-type 7Add BLAST87
Domaini845 – 1173Protein kinasePROSITE-ProRule annotationAdd BLAST329

Domaini

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

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0200. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118923.
HOGENOMiHOG000037949.
HOVERGENiHBG053432.
InParanoidiP35917.
KOiK05097.
OMAiCDTVAVK.
OrthoDBiEOG091G01TL.
PhylomeDBiP35917.
TreeFamiTF325768.

Family and domain databases

Gene3Di2.60.40.10. 9 hits.
InterProiIPR007110. 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]
PANTHERiPTHR24416:SF49. PTHR24416:SF49. 3 hits.
PfamiPF07679. I-set. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR01835. VEGFRECEPTR3.
SMARTiSM00409. IG. 6 hits.
SM00408. IGc2. 4 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 6 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50835. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P35917-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MQPGAALNLR LWLCLGLLQG LANGYSMTPP TLNITEDSYV IDTGDSLSIS
60 70 80 90 100
CRGQHPLEWT WPGAQEVLTT GGKDSEDTRV VHDCEGTEAR PYCKVLLLAQ
110 120 130 140 150
THANNTGSYH CYYKYIKARI EGTTAASTYV FVRDFKHPFI NKPDTLLVNR
160 170 180 190 200
KDSMWVPCLV SIPGLNITLR SQSSALHPDG QEVLWDDRRG MRVPTQLLRD
210 220 230 240 250
ALYLQCETTW GDQNFLSNLF VVHITGNELY DIQLYPKKSM ELLVGEKLVL
260 270 280 290 300
NCTVWAEFDS GVTFDWDYPG KQAERAKWVP ERRSQQTHTE LSSILTIHNV
310 320 330 340 350
SQNDLGPYVC EANNGIQRFR ESTEVIVHEK PFISVEWLKG PVLEATAGDE
360 370 380 390 400
LVKLPVKLAA YPPPEFQWYK DRKAVTGRHN PHALVLKEVT EASAGVYTLA
410 420 430 440 450
LWNSAAGLRQ NISLELVVNV PPHIHEKEAS SPSIYSRHSR QTLTCTAYGV
460 470 480 490 500
PQPLSVQWHW RPWTPCKTFA QRSLRRRQQR DGMPQCRDWK EVTTQDAVNP
510 520 530 540 550
IESLDSWTEF VEGKNKTVSK LVIQDANVSA MYKCVVVNKV GQDERLIYFY
560 570 580 590 600
VTTIPDGFSI ESEPSEDPLE GQSVRLSCRA DNYTYEHLRW YRLNLSTLHD
610 620 630 640 650
AQGNPLLLDC KNVHLFATPL EANLEEAEPG ARHATLSLNI PRVAPEDEGD
660 670 680 690 700
YVCEVQDRRS QDKHCHKKYL SVQALEAPRL TQNLTDLLVN VSDSLEMRCP
710 720 730 740 750
VAGAHVPSIV WYKDERLLEK ESGIDLADSN QRLSIQRVRE EDAGRYLCSV
760 770 780 790 800
CNAKGCVNSS ASVAVEGSED KGSMEIVILI GTGVIAVFFW VLLLLIFCNM
810 820 830 840 850
KRPAHADIKT GYLSIIMDPG EVPLEEQCEY LSYDASQWEF PRERLHLGRV
860 870 880 890 900
LGHGAFGKVV EASAFGINKG SSCDTVAVKM LKEGATASEH RALMSELKIL
910 920 930 940 950
IHIGNHLNVV NLLGACTKPN GPLMVIVEFC KYGNLSNFLR VKRDTFNPYA
960 970 980 990 1000
EKSPEQRRRF RAMVEGAKAD RRRPGSSDRA LFTRFLMGKG SARRAPLVQE
1010 1020 1030 1040 1050
AEDLWLSPLT MEDLVCYSFQ VARGMEFLAS RKCIHRDLAA RNILLSESDI
1060 1070 1080 1090 1100
VKICDFGLAR DIYKDPDYVR KGSARLPLKW MAPESIFDKV YTTQSDVWSF
1110 1120 1130 1140 1150
GVLLWEIFSL GASPYPGVQI NEEFCQRLKD GTRMRAPELA TPAIRHIMQS
1160 1170 1180 1190 1200
CWSGDPKARP AFSDLVEILG DLLQGGGWQE EEEERMALHS SQSSEEDGFM
1210 1220 1230 1240 1250
QASTTALHIT EADADDSPPS MHCHSLAARY YNCVSFPGRL ARGTKTPGSS
1260 1270 1280 1290 1300
RMKTFEELPM TPTTYKASMD NQTDSGMVLA SEEFEELESR HRPEGSFSCK
1310 1320 1330 1340 1350
GPGQHMDIPR GHPDPQGRRR RPTQGAQGGK VFYNNEYGEV SQPCTEGDCC
1360
PSAGSTFFAD SSY
Length:1,363
Mass (Da):153,016
Last modified:June 1, 1994 - v1
Checksum:iF1BF8A2BDEF99BE9
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L07296 mRNA. Translation: AAA40077.1.
CCDSiCCDS24618.1.
PIRiI58375.
RefSeqiNP_032055.1. NM_008029.3.
UniGeneiMm.3291.

Genome annotation databases

EnsembliENSMUST00000020617; ENSMUSP00000020617; ENSMUSG00000020357.
GeneIDi14257.
KEGGimmu:14257.
UCSCiuc007iqu.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L07296 mRNA. Translation: AAA40077.1.
CCDSiCCDS24618.1.
PIRiI58375.
RefSeqiNP_032055.1. NM_008029.3.
UniGeneiMm.3291.

3D structure databases

ProteinModelPortaliP35917.
SMRiP35917.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi199709. 5 interactors.
DIPiDIP-60714N.
IntActiP35917. 1 interactor.
MINTiMINT-5313593.
STRINGi10090.ENSMUSP00000020617.

Chemistry databases

BindingDBiP35917.
GuidetoPHARMACOLOGYi1814.

PTM databases

iPTMnetiP35917.
PhosphoSitePlusiP35917.

Proteomic databases

PaxDbiP35917.
PeptideAtlasiP35917.
PRIDEiP35917.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000020617; ENSMUSP00000020617; ENSMUSG00000020357.
GeneIDi14257.
KEGGimmu:14257.
UCSCiuc007iqu.2. mouse.

Organism-specific databases

CTDi2324.
MGIiMGI:95561. Flt4.

Phylogenomic databases

eggNOGiKOG0200. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118923.
HOGENOMiHOG000037949.
HOVERGENiHBG053432.
InParanoidiP35917.
KOiK05097.
OMAiCDTVAVK.
OrthoDBiEOG091G01TL.
PhylomeDBiP35917.
TreeFamiTF325768.

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.
ReactomeiR-MMU-195399. VEGF binds to VEGFR leading to receptor dimerization.

Miscellaneous databases

PROiP35917.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000020357.
CleanExiMM_FLT4.
ExpressionAtlasiP35917. baseline and differential.
GenevisibleiP35917. MM.

Family and domain databases

Gene3Di2.60.40.10. 9 hits.
InterProiIPR007110. 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]
PANTHERiPTHR24416:SF49. PTHR24416:SF49. 3 hits.
PfamiPF07679. I-set. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PRINTSiPR01835. VEGFRECEPTR3.
SMARTiSM00409. IG. 6 hits.
SM00408. IGc2. 4 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 6 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50835. 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]
ProtoNetiSearch...

Entry informationi

Entry nameiVGFR3_MOUSE
AccessioniPrimary (citable) accession number: P35917
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: November 2, 2016
This is version 170 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.