Vascular endothelial growth factor C

From Wikipedia, the free encyclopedia
VEGFC
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesVEGFC, Flt4-L, LMPH1D, VRP, vascular endothelial growth factor C, LMPHM4
External IDsOMIM: 601528 MGI: 109124 HomoloGene: 3962 GeneCards: VEGFC
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005429

NM_009506

RefSeq (protein)

NP_005420

NP_033532

Location (UCSC)Chr 4: 176.68 – 176.79 MbChr 8: 54.53 – 54.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000150630 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031520 - Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  11. ^ Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, et al. (May 2009). "Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism". Nature Medicine. 15 (5): 545–552. doi:10.1038/nm.1960. PMID 19412173. S2CID 10526891.
  12. ^ a b Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. (July 1997). "Proteolytic processing regulates receptor specificity and activity of VEGF-C". The EMBO Journal. 16 (13): 3898–3911. doi:10.1093/emboj/16.13.3898. PMC 1170014. PMID 9233800.
  13. ^ Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, et al. (June 2003). "The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis". The Journal of Clinical Investigation. 111 (11): 1723–1732. doi:10.1172/JCI17220. PMC 156106. PMID 12782675.
  14. ^ a b c Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, et al. (May 2014). "CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation". Circulation. 129 (19): 1962–1971. doi:10.1161/CIRCULATIONAHA.113.002779. PMID 24552833.
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  16. ^ Jha SK, Rauniyar K, Chronowska E, Mattonet K, Maina EW, Koistinen H, et al. (May 2019). "KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D". eLife. 8: 44478. doi:10.7554/eLife.44478. PMC 6588350. PMID 31099754.
  17. ^ Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, et al. (January 1998). "Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)". Proceedings of the National Academy of Sciences of the United States of America. 95 (2): 548–553. Bibcode:1998PNAS...95..548A. doi:10.1073/pnas.95.2.548. PMC 18457. PMID 9435229.
  18. ^ Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, et al. (January 2004). "Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins". Nature Immunology. 5 (1): 74–80. doi:10.1038/ni1013. PMID 14634646. S2CID 22078757.
  19. ^ Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, et al. (March 2005). "Vascular endothelial growth factor D is dispensable for development of the lymphatic system". Molecular and Cellular Biology. 25 (6): 2441–2449. doi:10.1128/MCB.25.6.2441-2449.2005. PMC 1061605. PMID 15743836.
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  22. ^ Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, et al. (March 2001). "Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin". Circulation Research. 88 (6): 623–629. doi:10.1161/01.RES.88.6.623. PMID 11282897. S2CID 28806663.
  23. ^ Honkonen KM, Visuri MT, Tervala TV, Halonen PJ, Koivisto M, Lähteenvuo MT, et al. (May 2013). "Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema". Annals of Surgery. 257 (5): 961–7. doi:10.1097/SLA.0b013e31826ed043. PMID 23013803. S2CID 2042145.
  24. ^ Brouillard P, Boon L, Vikkula M (March 2014). "Genetics of lymphatic anomalies". The Journal of Clinical Investigation. 124 (3): 898–904. doi:10.1172/JCI71614. PMC 3938256. PMID 24590274.
  25. ^ Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, et al. (October 2001). "A model for gene therapy of human hereditary lymphedema". Proceedings of the National Academy of Sciences of the United States of America. 98 (22): 12677–12682. Bibcode:2001PNAS...9812677K. doi:10.1073/pnas.221449198. PMC 60113. PMID 11592985.
  26. ^ Herantis Pharma (2014-07-21). "Lymfactin® for lymphedema". {{cite web}}: Missing or empty |url= (help)
  27. ^ Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. (February 2001). "Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis". Nature Medicine. 7 (2): 192–198. doi:10.1038/84643. PMID 11175850. S2CID 26090359.
  28. ^ Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. (February 2001). "Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis". The EMBO Journal. 20 (4): 672–682. doi:10.1093/emboj/20.4.672. PMC 145430. PMID 11179212.
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  31. ^ Heino TI, Kärpänen T, Wahlström G, Pulkkinen M, Eriksson U, Alitalo K, Roos C (November 2001). "The Drosophila VEGF receptor homolog is expressed in hemocytes". Mechanisms of Development. 109 (1): 69–77. doi:10.1016/S0925-4773(01)00510-X. PMID 11677054. S2CID 14074572.
  32. ^ Seipel K, Eberhardt M, Müller P, Pescia E, Yanze N, Schmid V (October 2004). "Homologs of vascular endothelial growth factor and receptor, VEGF and VEGFR, in the jellyfish Podocoryne carnea". Developmental Dynamics. 231 (2): 303–312. doi:10.1002/dvdy.20139. PMID 15366007. S2CID 42930371.

Further reading[edit]

External links[edit]

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