Atlas of Genetics and Cytogenetics in Oncology and Haematology

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FIGF (c-fos induced growth factor (vascular endothelial growth factor D))

Written2012-05Marina Rocchigiani, Salvatore Oliviero
Department of Molecular Biology, University of Siena, Italy

(Note : for Links provided by Atlas : click)


Other namesVEGF-D
LocusID (NCBI) 2277
Atlas_Id 40574
Location Xp22.2
Location_base_pair Starts at 15363713 and ends at 15402535 bp from pter ( according to hg19-Feb_2009)  [Mapping]


Description The VEGFD gene consists of 7 exons and spans 38865 bases on chromosome X in minus strand orientation.
The upstream promoter sequence does not contain a canonical TATA box. The promoter sequence contains an optimal AP-1 binding site at position -54 from the start site.
Transcription The mRNA transcribed from this gene is 2110 nucleotides long.


  The VEGF-D chain is a secreted protein synthesised as 354 amino acid precursor containing a signal peptide (AA:1-21), an N-propeptide (AA:22-88), a VHD (VEGF Homology Domain, AA:89-205) and a C-propeptide (AA:206-354).
Description VEGF-D is a member of the Platelet-Derived Growth Factor/Vascular Endothelial Growth Factor (PDGF/VEGF) family that contains a conserved domain of eight cysteine residues forming the typical cystine-knot structure involved in the formation of the biologically active dimer (Debinski et al., 2001; Rocchigiani et al., 1998; Yamada et al., 1997; Joukov et al., 1996). The human VEGF family consists of 5 members: VEGF-A, VEGF-B, VEGF-C, VEGF-D and Placental Growth Factor (PlGF) which differ in their ability to bind to VEGF receptors that are primarily expressed in endothelial cells: VEGFR1 (Flt1), VEGFR2 (KDR, Flk1), VEGFR3 (Flt4), neuropilin-1 and neuropilin-2. VEGFA binds to VEGFR1, VEGFR2, as well as neuropilin-1 and neuropilin-2, whereas PlGF and VEGFB bind only to VEGFR1 and neuropilin-1.
VEGF-C and VEGF-D, which share 23% amino acid sequence identity, are uniquely expressed as preproproteins that contain long N- and C-terminal propeptide extensions around the VEGF homology domain (VHD). The C-terminal amino acid sequenze show a pattern of spacing cysteine residues reminescent of the BR3P sequence. Proteolytic processing of the 354 aa VEGF-D preproprotein creates a secreted proprotein. Further processing by extracellular serine proteases, such as plasmin or furin-like proprotein convertases, forms mature VEGF-D consisting of non-covalently linked homodimers of the 117 aa VHD (Stacker et al., 1999; McColl et al., 2003; McColl et al., 2007). Human VEGF-D is ligand for VEGFR-2 and VEGFR-3.
VEGF-D is expressed in fibroblasts and its messenger is stabilized by cell contacts (Orlandini and Oliviero, 2001). Its receptor VEGFR3 is constitutively expressed in lymphatic endothelial cells and in vascular endothelial cells during angiogenesis and in endothelial precursors and in osteoblasts (Tammela et al., 2011; Orlandini et al., 2006).
VEGF-D and VEGFR-3 are expressed in the osteoblasts of the growing plate. The treatment of primary human osteoblasts with recombinant VEGF-D induces the expression of osteocalcin and the formation of mineralized nodules in a dose-dependent manner (Orlandini et al., 2006).
Expression It is expressed in adult lung, heart, muscle, and small intestine, and is most abundantly expressed in fetal lungs and skin.
VEGF-D expression in mouse fibroblasts is induced by cell interaction mediated by cadherin 11 (Orlandini et al., 2006; Avantaggiato et al., 1998).
Localisation Secreted in the extracellular medium.
Function Growth factor active in angiogenesis, lymphangiogenesis and endothelial cell growth, stimulating their proliferation and migration of blood cells. It may function in the formation 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 (Flk1) and VEGFR-3 (Flt4) receptors.
VEGFD controls the total length and complexity of dendrites both in cultured hippocampal neurons and in the adult mouse hippocampus (Mauceri et al., 2011).
VEGFD together with SDF1α and sFRP1 are major components of stromal cell-derived inducing activity of dopaminergic neurons (Schwartz et al., 2012).
Homology VEGF-D is highly conserved, it shares 94%, 95%, 99%, 97% and 93% aa identity with mouse, rat, equine, canine and bovine VEGF-D, respectively.


Note Single Nucleotide Polymorphism have been described in mRNA UTR, introns or in exons: see NCBI database.

Implicated in

Entity Lymphangioleiomyomatosis
Note VEGF-D prognostic marker for tumor growth and dissemination.
Disease High level VEGFD in patients with lymphangioleiomyomatosis.
Prognosis Serum VEGF-D may be a clinically useful diagnostic test that can distinguish sporadic lymphangioleiomyomatosis from other cystic and chylous lung diseases, potentially decreasing the need for lung biopsy (Young et al., 2008).
Entity Metastasis
Note VEGF-D-dependent regulation of the prostaglandin pathway induces lymphatic vessel dilation and subsequent increase of metastatic spread (Karnezis et al., 2012).
Entity Soft tissue sarcoma
Note VEGF-D significantly increases the migration of sarcoma cells through lymphatic endothelial monolayers. The VEGF-D-dependent induced migration through lymphatics might be the reason for relationship between VEGF-D expression and lymph node metastasis in soft tissue sarcomas (Yanagawa et al., 2012).


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. 1996 Jan 15;15(2):290-98.
PMID 8617204
Molecular cloning of a novel vascular endothelial growth factor, VEGF-D.
Yamada Y, Nezu J, Shimane M, Hirata Y.
Genomics. 1997 Jun 15;42(3):483-8.
PMID 9205122
Embryonic expression pattern of the murine figf gene, a growth factor belonging to platelet-derived growth factor/vascular endothelial growth factor family.
Avantaggiato V, Orlandini M, Acampora D, Oliviero S, Simeone A.
Mech Dev. 1998 May;73(2):221-4.
PMID 9622638
Human FIGF: cloning, gene structure, and mapping to chromosome Xp22.1 between the PIGA and the GRPR genes.
Rocchigiani M, Lestingi M, Luddi A, Orlandini M, Franco B, Rossi E, Ballabio A, Zuffardi O, Oliviero S.
Genomics. 1998 Jan 15;47(2):207-16.
PMID 9479493
Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers.
Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, Alitalo K, Achen MG.
J Biol Chem. 1999 Nov 5;274(45):32127-36.
PMID 10542248
VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme.
Debinski W, Slagle-Webb B, Achen MG, Stacker SA, Tulchinsky E, Gillespie GY, Gibo DM.
Mol Med. 2001 Sep;7(9):598-608.
PMID 11778649
In fibroblasts Vegf-D expression is induced by cell-cell contact mediated by cadherin-11.
Orlandini M, Oliviero S.
J Biol Chem. 2001 Mar 2;276(9):6576-81. Epub 2000 Dec 6.
PMID 11108717
Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D.
McColl BK, Baldwin ME, Roufail S, Freeman C, Moritz RL, Simpson RJ, Alitalo K, Stacker SA, Achen MG.
J Exp Med. 2003 Sep 15;198(6):863-8. Epub 2003 Sep 8.
PMID 12963694
Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation.
Orlandini M, Spreafico A, Bardelli M, Rocchigiani M, Salameh A, Nucciotti S, Capperucci C, Frediani B, Oliviero S.
J Biol Chem. 2006 Jun 30;281(26):17961-7. Epub 2006 Apr 19.
PMID 16624815
Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.
McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J, Nice EC, Harder KW, Roufail S, Hibbs ML, Rogers PA, Alitalo K, Stacker SA, Achen MG.
FASEB J. 2007 Apr;21(4):1088-98. Epub 2007 Jan 22.
PMID 17242158
Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis.
Young LR, Inoue Y, McCormack FX.
N Engl J Med. 2008 Jan 10;358(2):199-200.
PMID 18184970
Nuclear calcium-VEGFD signaling controls maintenance of dendrite arborization necessary for memory formation.
Mauceri D, Freitag HE, Oliveira AM, Bengtson CP, Bading H.
Neuron. 2011 Jul 14;71(1):117-30.
PMID 21745642
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 CA, Murtomaki A, Aranda E, Miura N, Yla-Herttuala S, Fruttiger M, Makinen T, Eichmann A, Pollard JW, Gerhardt H, Alitalo K.
Nat Cell Biol. 2011 Sep 11;13(10):1202-13. doi: 10.1038/ncb2331.
PMID 21909098
VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium.
Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, Rupasinghe TW, Tull DL, Baldwin ME, Sloan EK, Fox SB, Achen MG, Stacker SA.
Cancer Cell. 2012 Feb 14;21(2):181-95.
PMID 22340592
Stromal factors SDF1a, sFRP1, and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells.
Schwartz CM, Tavakoli T, Jamias C, Park SS, Maudsley S, Martin B, Phillips TM, Yao PJ, Itoh K, Ma W, Rao MS, Arenas E, Mattson MP.
J Neurosci Res. 2012 Jul;90(7):1367-81. doi: 10.1002/jnr.23064. Epub 2012 Apr 26.
PMID 22535492
Vascular endothelial growth factor-D is a key molecule that enhances lymphatic metastasis of soft tissue sarcomas.
Yanagawa T, Shinozaki T, Watanabe H, Saito K, Raz A, Takagishi K.
Exp Cell Res. 2012 Apr 15;318(7):800-8. Epub 2012 Feb 3.
PMID 22326461


This paper should be referenced as such :
Rocchigiani, M ; Oliviero, S
FIGF (c-fos induced growth factor (vascular endothelial growth factor D))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(11):809-812.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas)
  Soft Tissues: Lymphangioleiomyoma

External links

HGNC (Hugo)FIGF   3708
Entrez_Gene (NCBI)FIGF  2277  c-fos induced growth factor (vascular endothelial growth factor D)
GeneCards (Weizmann)FIGF
Ensembl hg19 (Hinxton)ENSG00000165197 [Gene_View]  chrX:15363713-15402535 [Contig_View]  FIGF [Vega]
Ensembl hg38 (Hinxton)ENSG00000165197 [Gene_View]  chrX:15363713-15402535 [Contig_View]  FIGF [Vega]
ICGC DataPortalENSG00000165197
Genatlas (Paris)FIGF
SOURCE (Princeton)FIGF
Genomic and cartography
GoldenPath hg19 (UCSC)FIGF  -     chrX:15363713-15402535 -  Xp22.31   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)FIGF  -     Xp22.31   [Description]    (hg38-Dec_2013)
EnsemblFIGF - Xp22.31 [CytoView hg19]  FIGF - Xp22.31 [CytoView hg38]
Mapping of homologs : NCBIFIGF [Mapview hg19]  FIGF [Mapview hg38]
Gene and transcription
Genbank (Entrez)AJ000185 AK223160 AK313173 BC027948 D89630
RefSeq transcript (Entrez)NM_004469
RefSeq genomic (Entrez)NC_000023 NC_018934 NG_012509 NT_167197 NW_004929438
Consensus coding sequences : CCDS (NCBI)FIGF
Cluster EST : UnigeneHs.11392 [ NCBI ]
CGAP (NCI)Hs.11392
Alternative Splicing : Fast-db (Paris)GSHG0031987
Alternative Splicing GalleryENSG00000165197
Gene ExpressionFIGF [ NCBI-GEO ]     FIGF [ SEEK ]   FIGF [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO43915 (Uniprot)
NextProtO43915  [Medical]  [Publications]
With graphics : InterProO43915
Splice isoforms : SwissVarO43915 (Swissvar)
Domaine pattern : Prosite (Expaxy)PDGF_1 (PS00249)    PDGF_2 (PS50278)   
Domains : Interpro (EBI)Cystine-knot_cytokine    PD_growth_factor_CS    PDGF/VEGF_dom   
Related proteins : CluSTrO43915
Domain families : Pfam (Sanger)PDGF (PF00341)   
Domain families : Pfam (NCBI)pfam00341   
Domain families : Smart (EMBL)PDGF (SM00141)  
DMDM Disease mutations2277
Blocks (Seattle)O43915
PDB (SRS)2XV7   
PDB (PDBSum)2XV7   
PDB (IMB)2XV7   
Human Protein AtlasENSG00000165197
Peptide AtlasO43915
Protein Interaction databases
IntAct (EBI)O43915
Ontologies - Pathways
Ontology : AmiGOangiogenesis  platelet degranulation  platelet-derived growth factor receptor binding  vascular endothelial growth factor receptor binding  extracellular region  extracellular space  blood coagulation  growth factor activity  cell proliferation  positive regulation of cell proliferation  membrane  cell differentiation  platelet activation  platelet alpha granule lumen  chemoattractant activity  protein homodimerization activity  vascular endothelial growth factor receptor 3 binding  vascular endothelial growth factor receptor signaling pathway  positive chemotaxis  induction of positive chemotaxis  positive regulation of cell division  positive regulation of mast cell chemotaxis  
Ontology : EGO-EBIangiogenesis  platelet degranulation  platelet-derived growth factor receptor binding  vascular endothelial growth factor receptor binding  extracellular region  extracellular space  blood coagulation  growth factor activity  cell proliferation  positive regulation of cell proliferation  membrane  cell differentiation  platelet activation  platelet alpha granule lumen  chemoattractant activity  protein homodimerization activity  vascular endothelial growth factor receptor 3 binding  vascular endothelial growth factor receptor signaling pathway  positive chemotaxis  induction of positive chemotaxis  positive regulation of cell division  positive regulation of mast cell chemotaxis  
Pathways : KEGGRas signaling pathway    Rap1 signaling pathway    Cytokine-cytokine receptor interaction    PI3K-Akt signaling pathway    Focal adhesion    Pathways in cancer   
REACTOMEO43915 [protein]
REACTOME PathwaysREACT_604 Hemostasis [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseFIGF
Atlas of Cancer Signalling NetworkFIGF
Wikipedia pathwaysFIGF
Gene fusions - Rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerFIGF [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FIGF
Exome Variant ServerFIGF
Genetic variants : HAPMAPFIGF
Genomic Variants (DGV)FIGF [DGVbeta]
ICGC Data PortalFIGF 
TCGA Data PortalFIGF 
Tumor PortalFIGF
TCGA Copy Number PortalFIGF
Somatic Mutations in Cancer : COSMICFIGF 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)X-chromosome gene database
DoCM (Curated mutations)FIGF
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
DECIPHER (Syndromes)X:15363713-15402535
CONAN: Copy Number AnalysisFIGF 
Mutations and Diseases : HGMDFIGF
NextProtO43915 [Medical]
Huge Navigator FIGF [HugePedia]  FIGF [HugeCancerGEM]
snp3D : Map Gene to Disease2277
DGIdb (Drug Gene Interaction db)FIGF
General knowledge
Homologs : HomoloGeneFIGF
Homology/Alignments : Family Browser (UCSC)FIGF
Phylogenetic Trees/Animal Genes : TreeFamFIGF
Chemical/Protein Interactions : CTD2277
Chemical/Pharm GKB GenePA28146
Clinical trialFIGF
Cancer Resource (Charite)ENSG00000165197
Other databases
PubMed104 Pubmed reference(s) in Entrez
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Nov 25 17:21:30 CET 2015

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