Vascular endothelial growth factor C

Vascular endothelial growth factor C
Rendering based on PDB 2X1W​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2X1W​, 2X1X​, 4BSK​
Identifiers
Symbols	VEGFC ; Flt4-L; LMPH1D; VRP
External IDs	OMIM: 601528 MGI: 109124 HomoloGene: 3962 GeneCards: VEGFC Gene
Gene ontology Molecular function • protein binding • growth factor activity • chemoattractant activity • vascular endothelial growth factor receptor 3 binding Cellular component • extracellular region • extracellular space • membrane • platelet alpha granule lumen Biological process • angiogenesis • positive regulation of cell-matrix adhesion • positive regulation of neuroblast proliferation • platelet degranulation • substrate-dependent cell migration • signal transduction • blood coagulation • positive regulation of cell proliferation • negative regulation of cell proliferation • organ morphogenesis • morphogenesis of embryonic epithelium • platelet activation • regulation of vascular endothelial growth factor receptor signaling pathway • positive regulation of protein autophosphorylation • response to drug • positive regulation of blood vessel endothelial cell migration • positive regulation of angiogenesis • negative regulation of blood pressure • vascular endothelial growth factor receptor signaling pathway • positive regulation of epithelial cell proliferation • positive regulation of protein secretion • positive regulation of peptidyl-tyrosine phosphorylation • positive chemotaxis • induction of positive chemotaxis • positive regulation of cell division • positive regulation of mast cell chemotaxis • positive regulation of lymphangiogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
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: 54.08 – 54.19 Mb
PubMed search

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.^[1]

Functions

The main function of VEGF-C is in lymphangiogenesis, where 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.^[2] Soon thereafter, it was shown to be a specific growth factor for lymphatic vessels in a variety of models.^[3][4] 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^[5] or its secondary receptor VEGFR-2. Apart from vascular targets, VEGF-C is also important for neural development^[6] and blood pressure regulation.^[7]

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).^[8] 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.^[9] However, the resulting protein is still held together by disulfide bonds and remains inactive (although it can bind already VEGFR-3).^[10] 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^[10] or plasmin.^[11] 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.^[8]

Relationship to VEGF-D

The closest structural and functional relative of VEGF-C is VEGF-D.^[12] However, at least in mice, VEGF-C is absolutely essential for the development of the lymphatic system,^[13] whereas VEGF-D appears to be not necessary at all.^[14] Whether this holds true for humans is unknown, because there are major differences between human and mouse VEGF-D.^[15]

Disease relevance

In a minority of lymphedema patients, the condition is caused by mutations in the VEGFC gene^[16] and VEGF-C is a potential treatment for lymphedema,^[17][18] even though the underlying molecular cause appears more often in the VEGF-Receptor-3 instead of VEGF-C itself.^[19] 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.^[20] Therefore VEGF-C is developed as a lymphedema drug under the name of Lymfactin.^[21] 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.^[10] While a lack of VEGF-C results in lymphedema, too much VEGF-C is implicated in tumor angiogenesis and metastasis. VEGF-C can act directly on blood vessels to promote tumor angiogenesis^[5][22] and it can promote lymphangiogenesis, which might result in increased metastasis.^[23]

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.^[24] 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^[25] and the PVFs in the jellyfish Podocoryne carnea for the development of the tentacles and the gastrovascular apparatus.^[26] However, the function of the PVF-1 of the nematode Caenorhabditis elegans is unknown^[24]

References

Further reading