VEGFD_HUMAN
ID VEGFD_HUMAN Reviewed; 354 AA.
AC O43915; B2R7Z3;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Vascular endothelial growth factor D {ECO:0000312|HGNC:HGNC:3708};
DE Short=VEGF-D;
DE AltName: Full=c-Fos-induced growth factor;
DE Short=FIGF;
DE Flags: Precursor;
GN Name=VEGFD {ECO:0000312|HGNC:HGNC:3708}; Synonyms=FIGF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lung;
RX PubMed=9205122; DOI=10.1006/geno.1997.4774;
RA Yamada Y., Nezu J., Shimane M., Hirata Y.;
RT "Molecular cloning of a novel vascular endothelial growth factor, VEGF-D.";
RL Genomics 42:483-488(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Lung;
RX PubMed=9479493; DOI=10.1006/geno.1997.5079;
RA Rocchigiani M., Lestingi M., Luddi A., Orlandini M., Franco B., Rossi E.,
RA Ballabio A., Zuffardi O., Oliviero S.;
RT "Human FIGF: cloning, gene structure, and mapping to chromosome Xp22.1
RT between the PIGA and the GRPR genes.";
RL Genomics 47:207-216(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9435229; DOI=10.1073/pnas.95.2.548;
RA Achen M.G., Jeltsch M., Kukk E., Maekinen T., Vitali A., Wilks A.F.,
RA Alitalo K., Stacker S.A.;
RT "Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine
RT kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).";
RL Proc. Natl. Acad. Sci. U.S.A. 95:548-553(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 89-94; 100-105 AND 206-213, AND PROTEOLYTIC PROCESSING.
RX PubMed=10542248; DOI=10.1074/jbc.274.45.32127;
RA Stacker S.A., Stenvers K.L., Caesar C., Vitali A., Domagala T., Nice E.C.,
RA Roufail S., Simpson R.J., Moritz R., Karpanen T., Alitalo K., Achen M.G.;
RT "Biosynthesis of vascular endothelial growth factor-D involves proteolytic
RT processing which generates non-covalent homodimers.";
RL J. Biol. Chem. 274:32127-32136(1999).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 92-195 OF MUTANT ALA-117,
RP FUNCTION, SUBUNIT, GLYCOSYLATION AT ASN-155 AND ASN-185, AND DISULFIDE
RP BONDS.
RX PubMed=21148085; DOI=10.1182/blood-2010-08-301549;
RA Leppanen V.M., Jeltsch M., Anisimov A., Tvorogov D., Aho K., Kalkkinen N.,
RA Toivanen P., Yla-Herttuala S., Ballmer-Hofer K., Alitalo K.;
RT "Structural determinants of vascular endothelial growth factor-D - receptor
RT binding and specificity.";
RL Blood 117:1507-1515(2011).
CC -!- FUNCTION: Growth factor active in angiogenesis, lymphangiogenesis and
CC endothelial cell growth, stimulating their proliferation and migration
CC and also has effects on the permeability of blood vessels. May function
CC in the formation of the venous and lymphatic vascular systems during
CC embryogenesis, and also in the maintenance of differentiated lymphatic
CC endothelium in adults. Binds and activates VEGFR-2 (KDR/FLK1) and
CC VEGFR-3 (FLT4) receptors. {ECO:0000269|PubMed:21148085}.
CC -!- SUBUNIT: Homodimer; non-covalent and antiparallel.
CC {ECO:0000269|PubMed:21148085}.
CC -!- INTERACTION:
CC O43915; Q15836: VAMP3; NbExp=4; IntAct=EBI-11750035, EBI-722343;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Highly expressed in lung, heart, small intestine
CC and fetal lung, and at lower levels in skeletal muscle, colon, and
CC pancreas.
CC -!- PTM: Undergoes a complex proteolytic maturation which generates a
CC variety of processed secreted forms with increased activity toward
CC VEGFR-3 and VEGFR-2. VEGF-D first form an antiparallel homodimer linked
CC by disulfide bonds before secretion. The fully processed VEGF-D is
CC composed mostly of two VEGF homology domains (VHDs) bound by non-
CC covalent interactions. {ECO:0000269|PubMed:10542248}.
CC -!- SIMILARITY: Belongs to the PDGF/VEGF growth factor family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FIGFID40574chXp22.html";
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DR EMBL; D89630; BAA24264.1; -; mRNA.
DR EMBL; Y12863; CAA73370.1; -; mRNA.
DR EMBL; Y12864; CAA73371.1; -; Genomic_DNA.
DR EMBL; Y12865; CAA73371.1; JOINED; Genomic_DNA.
DR EMBL; Y12866; CAA73371.1; JOINED; Genomic_DNA.
DR EMBL; Y12867; CAA73371.1; JOINED; Genomic_DNA.
DR EMBL; Y12868; CAA73371.1; JOINED; Genomic_DNA.
DR EMBL; Y12869; CAA73371.1; JOINED; Genomic_DNA.
DR EMBL; Y12870; CAA73371.1; JOINED; Genomic_DNA.
DR EMBL; AJ000185; CAA03942.1; -; mRNA.
DR EMBL; AK313173; BAG35990.1; -; mRNA.
DR EMBL; CH471074; EAW98885.1; -; Genomic_DNA.
DR EMBL; BC027948; AAH27948.1; -; mRNA.
DR CCDS; CCDS14166.1; -.
DR RefSeq; NP_004460.1; NM_004469.4.
DR PDB; 2XV7; X-ray; 2.90 A; A=92-195.
DR PDBsum; 2XV7; -.
DR AlphaFoldDB; O43915; -.
DR SMR; O43915; -.
DR BioGRID; 108567; 57.
DR CORUM; O43915; -.
DR IntAct; O43915; 6.
DR STRING; 9606.ENSP00000297904; -.
DR GlyGen; O43915; 4 sites, 1 O-linked glycan (1 site).
DR iPTMnet; O43915; -.
DR PhosphoSitePlus; O43915; -.
DR BioMuta; VEGFD; -.
DR MassIVE; O43915; -.
DR PaxDb; O43915; -.
DR PeptideAtlas; O43915; -.
DR PRIDE; O43915; -.
DR ProteomicsDB; 49231; -.
DR Antibodypedia; 8816; 622 antibodies from 37 providers.
DR DNASU; 2277; -.
DR Ensembl; ENST00000297904.4; ENSP00000297904.3; ENSG00000165197.5.
DR GeneID; 2277; -.
DR KEGG; hsa:2277; -.
DR MANE-Select; ENST00000297904.4; ENSP00000297904.3; NM_004469.5; NP_004460.1.
DR UCSC; uc004cwt.3; human.
DR CTD; 2277; -.
DR DisGeNET; 2277; -.
DR GeneCards; VEGFD; -.
DR HGNC; HGNC:3708; VEGFD.
DR HPA; ENSG00000165197; Tissue enhanced (lung).
DR MIM; 300091; gene.
DR neXtProt; NX_O43915; -.
DR OpenTargets; ENSG00000165197; -.
DR PharmGKB; PA28146; -.
DR VEuPathDB; HostDB:ENSG00000165197; -.
DR eggNOG; ENOG502QVIH; Eukaryota.
DR GeneTree; ENSGT00940000159726; -.
DR HOGENOM; CLU_061712_0_0_1; -.
DR InParanoid; O43915; -.
DR OMA; FHTRTCA; -.
DR OrthoDB; 1364454at2759; -.
DR PhylomeDB; O43915; -.
DR TreeFam; TF319554; -.
DR BRENDA; 3.4.21.46; 2681.
DR PathwayCommons; O43915; -.
DR Reactome; R-HSA-114608; Platelet degranulation.
DR Reactome; R-HSA-194313; VEGF ligand-receptor interactions.
DR Reactome; R-HSA-195399; VEGF binds to VEGFR leading to receptor dimerization.
DR SignaLink; O43915; -.
DR SIGNOR; O43915; -.
DR BioGRID-ORCS; 2277; 8 hits in 694 CRISPR screens.
DR ChiTaRS; VEGFD; human.
DR EvolutionaryTrace; O43915; -.
DR GeneWiki; C-fos_induced_growth_factor; -.
DR GenomeRNAi; 2277; -.
DR Pharos; O43915; Tbio.
DR PRO; PR:O43915; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; O43915; protein.
DR Bgee; ENSG00000165197; Expressed in right lung and 117 other tissues.
DR Genevisible; O43915; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IEA:InterPro.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0042056; F:chemoattractant activity; IDA:UniProtKB.
DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0005161; F:platelet-derived growth factor receptor binding; TAS:ProtInc.
DR GO; GO:0043185; F:vascular endothelial growth factor receptor 3 binding; IBA:GO_Central.
DR GO; GO:0005172; F:vascular endothelial growth factor receptor binding; IPI:UniProtKB.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; IEA:Ensembl.
DR GO; GO:0048144; P:fibroblast proliferation; IEA:Ensembl.
DR GO; GO:0050930; P:induction of positive chemotaxis; IDA:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IBA:GO_Central.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IBA:GO_Central.
DR GO; GO:0060754; P:positive regulation of mast cell chemotaxis; IDA:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IBA:GO_Central.
DR GO; GO:0009617; P:response to bacterium; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IBA:GO_Central.
DR GO; GO:0002040; P:sprouting angiogenesis; IBA:GO_Central.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0038084; P:vascular endothelial growth factor signaling pathway; IBA:GO_Central.
DR CDD; cd00135; PDGF; 1.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR004153; CXCXC_repeat.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR023581; PD_growth_factor_CS.
DR InterPro; IPR000072; PDGF/VEGF_dom.
DR Pfam; PF03128; CXCXC; 1.
DR Pfam; PF00341; PDGF; 1.
DR SMART; SM00141; PDGF; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00249; PDGF_1; 1.
DR PROSITE; PS50278; PDGF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Angiogenesis; Cleavage on pair of basic residues;
KW Developmental protein; Differentiation; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Growth factor; Mitogen; Reference proteome;
KW Repeat; Secreted; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..88
FT /note="Or 99 (in a minor form)"
FT /evidence="ECO:0000269|PubMed:10542248"
FT /id="PRO_0000023408"
FT CHAIN 89..205
FT /note="Vascular endothelial growth factor D"
FT /id="PRO_0000023409"
FT PROPEP 206..354
FT /id="PRO_0000023410"
FT REPEAT 222..237
FT /note="1; approximate"
FT REPEAT 258..273
FT /note="2"
FT REPEAT 277..293
FT /note="3"
FT REPEAT 301..318
FT /note="4"
FT REGION 222..318
FT /note="4 X 16 AA repeats of C-X(10)-C-X-C-X(1,3)-C"
FT CARBOHYD 155
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21148085"
FT CARBOHYD 185
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21148085"
FT CARBOHYD 287
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 111..153
FT /evidence="ECO:0000269|PubMed:21148085"
FT DISULFID 136
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:21148085"
FT DISULFID 142..189
FT /evidence="ECO:0000269|PubMed:21148085"
FT DISULFID 145
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:21148085"
FT DISULFID 146..191
FT /evidence="ECO:0000269|PubMed:21148085"
FT HELIX 93..108
FT /evidence="ECO:0007829|PDB:2XV7"
FT STRAND 110..119
FT /evidence="ECO:0007829|PDB:2XV7"
FT HELIX 120..123
FT /evidence="ECO:0007829|PDB:2XV7"
FT HELIX 127..129
FT /evidence="ECO:0007829|PDB:2XV7"
FT STRAND 133..143
FT /evidence="ECO:0007829|PDB:2XV7"
FT STRAND 152..166
FT /evidence="ECO:0007829|PDB:2XV7"
FT STRAND 169..171
FT /evidence="ECO:0007829|PDB:2XV7"
FT STRAND 178..192
FT /evidence="ECO:0007829|PDB:2XV7"
SQ SEQUENCE 354 AA; 40444 MW; 2048D769D735173E CRC64;
MYREWVVVNV FMMLYVQLVQ GSSNEHGPVK RSSQSTLERS EQQIRAASSL EELLRITHSE
DWKLWRCRLR LKSFTSMDSR SASHRSTRFA ATFYDIETLK VIDEEWQRTQ CSPRETCVEV
ASELGKSTNT FFKPPCVNVF RCGGCCNEES LICMNTSTSY ISKQLFEISV PLTSVPELVP
VKVANHTGCK CLPTAPRHPY SIIRRSIQIP EEDRCSHSKK LCPIDMLWDS NKCKCVLQEE
NPLAGTEDHS HLQEPALCGP HMMFDEDRCE CVCKTPCPKD LIQHPKNCSC FECKESLETC
CQKHKLFHPD TCSCEDRCPF HTRPCASGKT ACAKHCRFPK EKRAAQGPHS RKNP
