P35917 (VGFR3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

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):
Fms-like tyrosine kinase 4
Short name=FLT-4
Tyrosine-protein kinase receptor FLT4

Gene names

Name:	Flt4
Synonyms:	Flt-4, Vegfr3

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1363 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	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 process	Angiogenesis
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Domain	Immunoglobulin domain Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	lymphangiogenesis Inferred from mutant phenotype Ref.6. Source: UniProtKB negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara peptidyl-tyrosine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of ERK1 and ERK2 cascade Inferred from electronic annotation. Source: Compara positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara positive regulation of cell proliferation Inferred from genetic interaction PubMed 9247316. Source: MGI positive regulation of endothelial cell migration Inferred from electronic annotation. Source: Compara positive regulation of endothelial cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of protein kinase C signaling cascade Inferred from electronic annotation. Source: Compara positive regulation of protein phosphorylation Inferred from electronic annotation. Source: Compara positive regulation vascular endothelial growth factor production Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from electronic annotation. Source: Compara 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
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from electronic annotation. Source: InterPro nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW vascular endothelial growth factor-activated receptor activity Inferred from genetic interaction PubMed 9247316. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Potential
	Chain	25 – 1363	1339	Vascular endothelial growth factor receptor 3		PRO_0000016777
Regions
	Topological domain	25 – 775	751	Extracellular Potential
	Transmembrane	776 – 796	21	Helical; Potential
	Topological domain	797 – 1363	567	Cytoplasmic Potential
	Domain	44 – 118	75	Ig-like C2-type 1
	Domain	151 – 213	63	Ig-like C2-type 2
	Domain	230 – 326	97	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	830	1	Phosphotyrosine; by SRC By similarity
	Modified residue	833	1	Phosphotyrosine; by SRC By similarity
	Modified residue	1063	1	Phosphotyrosine; by autocatalysis and SRC By similarity
	Modified residue	1068	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1230	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1231	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1265	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1333	1	Phosphotyrosine; by autocatalysis and SRC By similarity
	Modified residue	1337	1	Phosphotyrosine; by autocatalysis and SRC By similarity
	Modified residue	1363	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...) Potential
	Glycosylation	582	1	N-linked (GlcNAc...) Ref.4
	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		By similarity
	Disulfide bond	158 ↔ 206		By similarity
	Disulfide bond	252 ↔ 310		By similarity
	Disulfide bond	445 ↔ 534		By similarity
	Disulfide bond	578 ↔ 653		By similarity
	Disulfide bond	699 ↔ 751		By similarity

Sequences

	Sequence		Length	Mass (Da)
	P35917 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: F1BF8A2BDEF99BE9	FASTA	1,363	153,016
	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

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY. 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. , 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.
IPI	IPI00273133.
PIR	I58375.
RefSeq	NP_032055.1. NM_008029.3.
UniGene	Mm.3291.
3D structure databases
ProteinModelPortal	P35917.
SMR	P35917. Positions 27-765, 821-1223.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000020617.
PTM databases
PhosphoSite	P35917.
Proteomic databases
PaxDb	P35917.
PRIDE	P35917.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000020617; ENSMUSP00000020617; ENSMUSG00000020357.
GeneID	14257.
KEGG	mmu:14257.
Organism-specific databases
CTD	2324.
MGI	MGI:95561. Flt4.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000037949.
HOVERGEN	HBG053432.
InParanoid	P35917.
KO	K05097.
OMA	QINEEFC.
OrthoDB	EOG49W2DJ.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
ArrayExpress	P35917.
Bgee	P35917.
CleanEx	MM_FLT4.
Genevestigator	P35917.
GermOnline	ENSMUSG00000020357. Mus musculus.
Family and domain databases
Gene3D	2.60.40.10. 9 hits.
InterPro	IPR007110. Ig-like_dom. IPR013783. Ig-like_fold. IPR013098. Ig_I-set. IPR003599. Ig_sub. IPR003598. Ig_sub2. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_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. Tyr_kinase_VEGFR3_rcpt_N. IPR009134. Tyr_kinase_VEGFR_rcpt_N. [Graphical view]
Pfam	PF07679. I-set. 2 hits. PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
PRINTS	PR01832. VEGFRECEPTOR. PR01835. VEGFRECEPTR3.
SMART	SM00409. IG. 4 hits. SM00408. IGc2. 2 hits. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS50835. 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]
ProtoNet	Search...
Other
BindingDB	P35917.
ChEMBL	CHEMBL4758.
NextBio	285591.
SOURCE	Search...

Entry information

Entry name

VGFR3_MOUSE

Accession

Primary (citable) accession number: P35917

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 133 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program