P49767 (VEGFC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Vascular endothelial growth factor C
Short name=VEGF-C

Alternative name(s):
Flt4 ligand
Short name=Flt4-L
Vascular endothelial growth factor-related protein
Short name=VRP

Gene names

Name:

VEGFC

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	419 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	Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates VEGFR-2 (KDR/FLK1) and VEGFR-3 (FLT4) receptors. Ref.11
Subunit structure	Homodimer; non-covalent and antiparallel. Ref.11
Subcellular location	Secreted.
Tissue specificity	Spleen, lymph node, thymus, appendix, bone marrow, heart, placenta, ovary, skeletal muscle, prostate, testis, colon and small intestine and fetal liver, lung and kidney, but not in peripheral blood lymphocyte.
Post-translational modification	Undergoes a complex proteolytic maturation which generates a variety of processed secreted forms with increased activity toward VEGFR-3, but only the fully processed form could activate VEGFR-2. VEGF-C first form an antiparallel homodimer linked by disulfide bonds. Before secretion, a cleavage occurs between Arg-227 and Ser-228 producing a heterotetramer. The next extracellular step of the processing removes the N-terminal propeptide. Finally the mature VEGF-C is composed mostly of two VEGF homology domains (VHDs) bound by non-covalent interactions.
Sequence similarities	Belongs to the PDGF/VEGF growth factor family.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation
Cellular component	Secreted
Domain	Repeat Signal
Molecular function	Developmental protein Growth factor Mitogen
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW induction of positive chemotaxis Inferred from direct assay PubMed 19275959. Source: UniProtKB morphogenesis of embryonic epithelium Inferred from electronic annotation. Source: Compara negative regulation of blood pressure Inferred from electronic annotation. Source: Compara organ morphogenesis Inferred from electronic annotation. Source: Compara platelet activation Traceable author statement. Source: Reactome platelet degranulation Traceable author statement. Source: Reactome positive regulation of blood vessel endothelial cell migration Inferred from electronic annotation. Source: Compara positive regulation of cell division Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of cell proliferation Traceable author statement Ref.1. Source: ProtInc positive regulation of epithelial cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of lymphangiogenesis Inferred from electronic annotation. Source: Compara positive regulation of mast cell chemotaxis Inferred from direct assay PubMed 19275959. Source: UniProtKB positive regulation of neuroblast proliferation Inferred from electronic annotation. Source: Compara positive regulation of protein autophosphorylation Inferred from electronic annotation. Source: Compara positive regulation of protein secretion Inferred from electronic annotation. Source: Compara regulation of vascular endothelial growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara substrate-dependent cell migration Traceable author statement Ref.1. Source: ProtInc vascular endothelial growth factor receptor signaling pathway Traceable author statement. Source: Reactome
Cellular_component	extracellular region Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: Compara membrane Inferred from electronic annotation. Source: InterPro platelet alpha granule lumen Traceable author statement. Source: Reactome
Molecular_function	chemoattractant activity Inferred from direct assay PubMed 19275959. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FLT4	P35916	2	EBI-3405539,EBI-1005467

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 31

31

Ref.9 Ref.10

Propeptide

32 – 111

80

Or 102

PRO_0000023400

Chain

112 – 227

116

Vascular endothelial growth factor C

PRO_0000023401

Propeptide

228 – 419

192

PRO_0000023402

Regions

Repeat

280 – 295

16

1

Repeat

304 – 319

16

2

Repeat

328 – 343

16

3

Repeat

347 – 362

16

4

Region

280 – 362

83

4 X 16 AA repeats of C-X(10)-C-X-C-X(1,3)-C

Amino acid modifications

Glycosylation

175

1

N-linked (GlcNAc...) Ref.11

Glycosylation

205

1

N-linked (GlcNAc...) Ref.11

Glycosylation

240

1

N-linked (GlcNAc...) Potential

Disulfide bond

131 ↔ 173

Ref.11

Disulfide bond

156

Interchain Ref.11

Disulfide bond

162 ↔ 209

Ref.11

Disulfide bond

165

Interchain Ref.11

Disulfide bond

166 ↔ 211

Ref.11

Experimental info

Mutagenesis

227

1

R → S: No proteolytic processing and lower effect on VEGFR-2 and VEGFR-3. Ref.9

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

419

Helix Strand Turn

Details...

Helix

117 – 129

13

Beta strand

130 – 139

10

Turn

140 – 142

3

Beta strand

151 – 163

13

Beta strand

167 – 170

4

Beta strand

172 – 188

17

Beta strand

190 – 194

5

Beta strand

197 – 212

16

Sequences

	Sequence		Length	Mass (Da)
	P49767 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 9F598719DB3E014F	FASTA	419	46,883
	10 20 30 40 50 60 MHLLGFFSVA CSLLAAALLP GPREAPAAAA AFESGLDLSD AEPDAGEATA YASKDLEEQL 70 80 90 100 110 120 RSVSSVDELM TVLYPEYWKM YKCQLRKGGW QHNREQANLN SRTEETIKFA AAHYNTEILK 130 140 150 160 170 180 SIDNEWRKTQ CMPREVCIDV GKEFGVATNT FFKPPCVSVY RCGGCCNSEG LQCMNTSTSY 190 200 210 220 230 240 LSKTLFEITV PLSQGPKPVT ISFANHTSCR CMSKLDVYRQ VHSIIRRSLP ATLPQCQAAN 250 260 270 280 290 300 KTCPTNYMWN NHICRCLAQE DFMFSSDAGD DSTDGFHDIC GPNKELDEET CQCVCRAGLR 310 320 330 340 350 360 PASCGPHKEL DRNSCQCVCK NKLFPSQCGA NREFDENTCQ CVCKRTCPRN QPLNPGKCAC 370 380 390 400 410 ECTESPQKCL LKGKKFHHQT CSCYRRPCTN RQKACEPGFS YSEEVCRCVP SYWKRPQMS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases." Joukov V., Pajusola K., Kaipainen A., Chilov D., Lahtinen I., Kukk E., Saksela O., Kalkkinen N., Alitalo K. EMBO J. 15:290-298(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 103-120.
[2]	Erratum Joukov V., Pajusola K., Kaipainen A., Chilov D., Lahtinen I., Kukk E., Saksela O., Kalkkinen N., Alitalo K. EMBO J. 15:1751-1751(1996) [PubMed] [Europe PMC] [Abstract]
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Glial tumor.
[4]	"Characterization of murine Flt4 ligand/VEGF-C." Fitz L.J., Morris J.C., Towler P., Long A., Burgess P., Greco R., Wang J., Gassaway R., Nickbarg E., Kovacic S., Ciarletta A., Giannotti J., Finnerty H., Zollner R., Beier D.R., Leak L.V., Turner K.J., Wood C.R. Oncogene 15:613-618(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Trachea.
[6]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skin and Urinary bladder.
[9]	"Proteolytic processing regulates receptor specificity and activity of VEGF-C." Joukov V., Sorsa T., Kumar V., Jeltsch M., Claesson-Welsh L., Cao Y., Saksela O., Kalkkinen N., Alitalo K. EMBO J. 16:3898-3911(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 32-41; 112-121 AND 228-233, MUTAGENESIS OF ARG-227.
[10]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 32-46.
[11]	"Structural determinants of growth factor binding and specificity by VEGF receptor 2." Leppanen V.M., Prota A.E., Jeltsch M., Anisimov A., Kalkkinen N., Strandin T., Lankinen H., Goldman A., Ballmer-Hofer K., Alitalo K. Proc. Natl. Acad. Sci. U.S.A. 107:2425-2430(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 112-215 IN COMPLEX WITH KDR, FUNCTION, DISULFIDE BONDS, GLYCOSYLATION AT ASN-175 AND ASN-205, SUBUNIT.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X94216 mRNA. Translation: CAA63907.1.
U43142 mRNA. Translation: AAA85214.1.
U58111 mRNA. Translation: AAB02909.1.
AK313879 mRNA. Translation: BAG36605.1.
AC092673 Genomic DNA. No translation available.
AC093801 Genomic DNA. No translation available.
CH471056 Genomic DNA. Translation: EAX04717.1.
BC035212 mRNA. Translation: AAH35212.1.
BC063685 mRNA. Translation: AAH63685.1.

IPI

IPI00028076.

PIR

S69207.

RefSeq

NP_005420.1. NM_005429.2.

UniGene

Hs.435215.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2X1W	X-ray	2.70	A/B/C/D	112-215	[»]
2X1X	X-ray	3.10	E	112-215	[»]

ProteinModelPortal

P49767.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-5738N.

IntAct

P49767. 1 interaction.

STRING

9606.ENSP00000280193.

Protein family/group databases

TCDB

9.B.88.2.1. selenoprotein P hydrogen selenide uptake protein (SelP) family.

PTM databases

PhosphoSite

P49767.

Polymorphism databases

DMDM

1718154.

Proteomic databases

PaxDb

P49767.

PRIDE

P49767.

Protocols and materials databases

DNASU

7424.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000280193; ENSP00000280193; ENSG00000150630.

GeneID

7424.

KEGG

hsa:7424.

UCSC

uc003ius.1. human.

Organism-specific databases

CTD

7424.

GeneCards

GC04M177604.

HGNC

HGNC:12682. VEGFC.

MIM

601528. gene.

neXtProt

NX_P49767.

PharmGKB

PA37304.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG79308.

HOGENOM

HOG000231512.

HOVERGEN

HBG073119.

InParanoid

P49767.

KO

K05449.

OrthoDB

EOG4D7Z62.

Enzyme and pathway databases

Pathway_Interaction_DB

vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.
lymphangiogenesis_pathway. VEGFR3 signaling in lymphatic endothelium.

Reactome

REACT_111102. Signal Transduction.
REACT_604. Hemostasis.

Gene expression databases

Bgee

P49767.

CleanEx

HS_VEGFC.

Genevestigator

P49767.

GermOnline

ENSG00000150630. Homo sapiens.

Family and domain databases

InterPro

IPR004153. CXCXC_repeat.
IPR000072. PD_growth_factor.
IPR023581. PD_growth_factor_CS.
[Graphical view]

Pfam

PF03128. CXCXC. 3 hits.
PF00341. PDGF. 1 hit.
[Graphical view]

SMART

SM00141. PDGF. 1 hit.
[Graphical view]

PROSITE

PS00249. PDGF_1. 1 hit.
PS50278. PDGF_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P49767.

GenomeRNAi

7424.

NextBio

29082.

PMAP-CutDB

P49767.

SOURCE

Search...

Entry information

Entry name

VEGFC_HUMAN

Accession

Primary (citable) accession number: P49767
Secondary accession number(s): B2R9Q8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 121 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.