Vascular endothelial growth factor C

VEGFC
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2X1W, 2X1X, 4BSK
Identifiers
Aliases	VEGFC, Flt4-L, LMPH1D, VRP, vascular endothelial growth factor C, LMPHM4
External IDs	OMIM: 601528 MGI: 109124 HomoloGene: 3962 GeneCards: VEGFC
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q34.3 Start 176,683,538 bp[1] End 176,792,922 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 B1.3 Start 54,530,641 bp[2] End 54,640,131 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium right lobe of thyroid gland left lobe of thyroid gland right lung parietal pleura visceral pleura pericardium subcutaneous adipose tissue lactiferous duct upper lobe of left lung Top expressed in external carotid artery internal carotid artery semi-lunar valve left lung lobe abdominal wall endocardial cushion aortic valve conjunctival fornix ascending aorta dermis More reference expression data BioGPS More reference expression data
Gene ontology Molecular function chemoattractant activity protein binding growth factor activity vascular endothelial growth factor receptor 3 binding vascular endothelial growth factor receptor binding Cellular component extracellular region membrane platelet alpha granule lumen extracellular space Biological process negative regulation of cell population proliferation positive regulation of neuroblast proliferation positive regulation of protein secretion substrate-dependent cell migration signal transduction positive regulation of protein autophosphorylation multicellular organism development morphogenesis of embryonic epithelium positive regulation of cell-matrix adhesion positive regulation of mast cell chemotaxis positive regulation of blood vessel endothelial cell migration positive regulation of cell division induction of positive chemotaxis platelet degranulation positive regulation of peptidyl-tyrosine phosphorylation negative regulation of blood pressure positive regulation of cell population proliferation positive regulation of lymphangiogenesis regulation of vascular endothelial growth factor receptor signaling pathway cell differentiation positive regulation of epithelial cell proliferation animal organ morphogenesis positive chemotaxis angiogenesis response to hypoxia positive regulation of endothelial cell proliferation positive regulation of angiogenesis cellular response to leukemia inhibitory factor vascular endothelial growth factor receptor signaling pathway regulation of signaling receptor activity positive regulation of protein phosphorylation sprouting angiogenesis vascular endothelial growth factor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7424 22341 Ensembl ENSG00000150630 ENSMUSG00000031520 UniProt P49767 P97953 RefSeq (mRNA) NM_005429 NM_009506 RefSeq (protein) NP_005420 NP_033532 Location (UCSC) Chr 4: 176.68 – 176.79 Mb Chr 8: 54.53 – 54.64 Mb PubMed search [3] [4]
Wikidata
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Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34.^[5]

Functions

The main function of VEGF-C is to promote the growth of lymphatic vessels (lymphangiogenesis). It acts on lymphatic endothelial cells (LECs) primarily via its receptor VEGFR-3 promoting survival, growth and migration. It was discovered in 1996 as a ligand for the orphan receptor VEGFR-3.^[6] Soon thereafter, it was shown to be a specific growth factor for lymphatic vessels in a variety of models.^[7][8] However, in addition to its effect on lymphatic vessels, it can also promote the growth of blood vessels and regulate their permeability. The effect on blood vessels can be mediated via its primary receptor VEGFR-3^[9] or its secondary receptor VEGFR-2. Apart from vascular targets, VEGF-C is also important for neural development^[10] and blood pressure regulation.^[11]

Biosynthesis

VEGF-C is a dimeric, secreted protein, which undergoes a complex proteolytic maturation resulting in multiple processed forms. After translation, VEGF-C consists of three domains: the central VEGF homology domain (VHD), the N-terminal domain (propeptide) and a C-terminal domain (propeptide).^[12] It is referred to as "uncleaved VEGF-C" and has a size of approximately 58 kDa. The first cleavage (which happens already before secretion) occurs between the VHD and the C-terminal domain and is mediated by proprotein convertases.^[13] However, the resulting protein is still held together by disulfide bonds and remains inactive (although it can bind already VEGFR-3).^[14] This form is referred to as "intermediate form" or pro-VEGF-C and it consists of two polypeptide chains of 29 and 31 kDa. In order to activate VEGF-C, a second cleavage has to occur between the N-terminal propeptide and the VHD. This cleavage can be performed either by ADAMTS3,^[14] plasmin,^[15] KLK3/PSA or cathepsin D.^[16] With progressing maturation, the affinity of VEGF-C for both VEGFR-2 and VEGFR-3 increases and only the fully processed, mature forms of VEGF-C have a significant affinity for VEGFR-2.^[12]

Relationship to VEGF-D

The closest structural and functional relative of VEGF-C is VEGF-D.^[17] However, at least in mice, VEGF-C is absolutely essential for the development of the lymphatic system,^[18] whereas VEGF-D appears to be unnecessary.^[19] Whether this holds true for humans is unknown, because there are major differences between human and mouse VEGF-D.^[20]

Disease relevance

In a minority of lymphedema patients, the condition is caused by mutations in the VEGFC gene^[21] and VEGF-C is a potential treatment for lymphedema,^[22][23] even though the underlying molecular cause appears more often in the VEGF-Receptor-3 instead of VEGF-C itself.^[24] Because in Milroy's disease (Hereditary lymphedema type I), only one allele is mutated, not all VEGFR-3 molecules are non-functional and it is thought, that high amounts of VEGF-C can compensate for the mutated, nonfunctional receptors by increasing the signaling levels of the remaining functional receptors.^[25] Therefore, VEGF-C is developed as a lymphedema drug under the name of Lymfactin.^[26] Also indirectly VEGF-C can be responsible for hereditary lymphedema: The rare Hennekam syndrome can result from the inability of the mutated CCBE1 to assist the ADAMTS3 protease in activating VEGF-C.^[14] While lack of VEGF-C results in lymphedema, VEGF-C production is implicated in tumor lymphangiogenesis and metastasis. Expression of VEGF-C by tumors induces peri-tumoral and intratumoral lymphangiogenesis what potently promotes metastatic dissemination of tumor cells.^[27][28] VEGF-C primarily stimulates lymphangiogenesis by activating VEGFR-3, yet under certain conditions it can also act directly on blood vessels to promote tumor angiogenesis.^[9][29]

Evolution

The PDGF family is so closely related to the VEGF family that the two are sometimes grouped together as the PDGF/VEGF family. In invertebrates, molecules from this families are not easily distinguished from each other and are collectively referred to as PVFs (PDGF/VEGF-like growth factors.^[30] The comparison of human VEGFs with these PVFs allows conclusions on the structure of the ancestral molecules, which appear more closely related to today's lymphangiogenic VEGF-C than to the other members of the VEGF family and despite their large evolutionary distance are still able to interact with human VEGF receptors. The PVFs in Drosophila melanogaster have functions for the migration of hemocytes^[31] and the PVFs in the jellyfish Podocoryne carnea for the development of the tentacles and the gastrovascular apparatus.^[32] However, the function of the PVF-1 of the nematode Caenorhabditis elegans is unknown^[30]

References

Further reading

External links

• Overview of all the structural information available in the PDB for UniProt: P49767 (Vascular endothelial growth factor C) at the PDBe-KB.