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

1. Paavonen K, Horelli-Kuitunen N, Chilov D, Kukk E, Pennanen S, Kallioniemi OP, Pajusola K, Olofsson B, Eriksson U, Joukov V, Palotie A, Alitalo K (Mar 1996). "Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively". Circulation 93 (6): 1079–1082. doi:10.1161/01.CIR.93.6.1079. PMID 8653826.
2. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (Jan 1996). "A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases". The EMBO Journal 15 (2): 290–298. PMC 449944. PMID 8617204.
3. Oh SJ, Jeltsch MM, Birkenhäger R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (Aug 1997). "VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane". Developmental Biology 188 (1): 96–109. doi:10.1006/dbio.1997.8639. PMID 9245515.
4. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (May 1997). "Hyperplasia of lymphatic vessels in VEGF-C transgenic mice". Science 276 (5317): 1423–1425. doi:10.1126/science.276.5317.1423. PMID 9162011.
5. Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (Jul 2008). "Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation". Nature 454 (7204): 656–660. doi:10.1038/nature07083. PMID 18594512.
6. Le Bras B, Barallobre MJ, Homman-Ludiye J, Ny A, Wyns S, Tammela T, Haiko P, Karkkainen MJ, Yuan L, Muriel MP, Chatzopoulou E, Bréant C, Zalc B, Carmeliet P, Alitalo K, Eichmann A, Thomas JL (Mar 2006). "VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain". Nature Neuroscience 9 (3): 340–348. doi:10.1038/nn1646. PMID 16462734.
7. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J (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.
8. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (Jul 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.
9. Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, Seidah NG, Khatib AM (Jun 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. PMID 12782675.
10. Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K (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.
11. McColl BK, Baldwin ME, Roufail S, Freeman C, Moritz RL, Simpson RJ, Alitalo K, Stacker SA, Achen MG (Sep 2003). "Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D". The Journal of Experimental Medicine 198 (6): 863–868. doi:10.1084/jem.20030361. PMC 2194198. PMID 12963694.
12. Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (Jan 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. doi:10.1073/pnas.95.2.548. PMC 18457. PMID 9435229.
13. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (Jan 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.
14. Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG (Mar 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. PMID 15743836.
15. Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG (Jun 2001). "The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man". The Journal of Biological Chemistry 276 (22): 19166–19171. doi:10.1074/jbc.M100097200. PMID 11279005.
16. Balboa-Beltran E, Fernández-Seara MJ, Pérez-Muñuzuri A, Lago R, García-Magán C, Couce ML, Sobrino B, Amigo J, Carracedo A, Barros F (Jul 2014). "A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease". Journal of Medical Genetics 51 (7): –2013–102020. doi:10.1136/jmedgenet-2013-102020. PMID 24744435.
17. Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K (Mar 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.
18. Honkonen KM, Visuri MT, Tervala TV, Halonen PJ, Koivisto M, Lähteenvuo MT, Alitalo KK, Ylä-Herttuala S, Saaristo AM (May 2013). "Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema". Annals of Surgery 257 (5): 961–967. doi:10.1097/SLA.0b013e31826ed043. PMID 23013803.
19. Brouillard P, Boon L, Vikkula M (Mar 2014). "Genetics of lymphatic anomalies". The Journal of Clinical Investigation 124 (3): 898–904. doi:10.1172/JCI71614. PMID 24590274.
20. Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K (Oct 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. doi:10.1073/pnas.221449198. PMID 11592985.
21. Herantis Pharma (2014-07-21). "Lymfactin® for lymphedema".
22. Tvorogov D, Anisimov A, Zheng W, Leppänen VM, Tammela T, Laurinavicius S, Holnthoner W, Heloterä H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala PM, Alitalo K (Dec 2010). "Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization". Cancer Cell 18 (6): 630–640. doi:10.1016/j.ccr.2010.11.001. PMID 21130043.
23. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (Feb 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. PMID 11179212.
24. Tarsitano M, De Falco S, Colonna V, McGhee JD, Persico MG (Feb 2006). "The C. elegans pvf-1 gene encodes a PDGF/VEGF-like factor able to bind mammalian VEGF receptors and to induce angiogenesis". FASEB Journal 20 (2): 227–233. doi:10.1096/fj.05-4147com. PMID 16449794.
25. Heino TI, Kärpänen T, Wahlström G, Pulkkinen M, Eriksson U, Alitalo K, Roos C (Nov 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.
26. Seipel K, Eberhardt M, Müller P, Pescia E, Yanze N, Schmid V (Oct 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.

Further reading

• Orpana A, Salven P (Feb 2002). "Angiogenic and lymphangiogenic molecules in hematological malignancies". Leukemia & Lymphoma 43 (2): 219–24. doi:10.1080/10428190290005964. PMID 11999550.
• Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (Jan 1996). "A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases". The EMBO Journal 15 (2): 290–98. PMC 449944. PMID 8617204.
• Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (Apr 1996). "A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases". The EMBO Journal 15 (7): 1751. PMC 450088. PMID 8612600.
• Paavonen K, Horelli-Kuitunen N, Chilov D, Kukk E, Pennanen S, Kallioniemi OP, Pajusola K, Olofsson B, Eriksson U, Joukov V, Palotie A, Alitalo K (Mar 1996). "Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively". Circulation 93 (6): 1079–82. doi:10.1161/01.cir.93.6.1079. PMID 8653826.
• Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI (Mar 1996). "Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4". Proceedings of the National Academy of Sciences of the United States of America 93 (5): 1988–92. doi:10.1073/pnas.93.5.1988. PMC 39896. PMID 8700872.
• Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (Jul 1997). "Proteolytic processing regulates receptor specificity and activity of VEGF-C". The EMBO Journal 16 (13): 3898–911. doi:10.1093/emboj/16.13.3898. PMC 1170014. PMID 9233800.
• Fitz LJ, Morris JC, Towler P, Long A, Burgess P, Greco R, Wang J, Gassaway R, Nickbarg E, Kovacic S, Ciarletta A, Giannotti J, Finnerty H, Zollner R, Beier DR, Leak LV, Turner KJ, Wood CR (Jul 1997). "Characterization of murine Flt4 ligand/VEGF-C". Oncogene 15 (5): 613–8. doi:10.1038/sj.onc.1201191. PMID 9247316.
• Dunk C, Ahmed A (Apr 2001). "Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast". Histology and Histopathology 16 (2): 359–75. PMID 11332691.
• Dias S, Choy M, Alitalo K, Rafii S (Mar 2002). "Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy". Blood 99 (6): 2179–84. doi:10.1182/blood.V99.6.2179. PMID 11877295.
• Ueda M, Terai Y, Yamashita Y, Kumagai K, Ueki K, Yamaguchi H, Akise D, Hung YC, Ueki M (Mar 2002). "Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas". International Journal of Cancer. Journal International Du Cancer 98 (3): 335–43. doi:10.1002/ijc.10193. PMID 11920583.
• Witte D, Thomas A, Ali N, Carlson N, Younes M (2002). "Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma". Anticancer Research 22 (3): 1463–6. PMID 12168824.
• Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (Sep 2002). "Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis". The American Journal of Pathology 161 (3): 947–56. doi:10.1016/S0002-9440(10)64255-1. PMC 1867252. PMID 12213723.
• Shin HY, Smith ML, Toy KJ, Williams PM, Bizios R, Gerritsen ME (Dec 2002). "VEGF-C mediates cyclic pressure-induced endothelial cell proliferation". Physiological Genomics 11 (3): 245–51. doi:10.1152/physiolgenomics.00068.2002. PMID 12388793.
• Yu DH, Wen YM, Sun JD, Wei SL, Xie HP, Pang FH (Mar 2002). "[Relationship among expression of vascular endothelial growth factor-C(VEGF-C), angiogenesis, lymphangiogenesis, and lymphatic metastasis in oral cancer]". Ai Zheng = Aizheng = Chinese Journal of Cancer 21 (3): 319–22. PMID 12452004.
• Nakashima T, Kondoh S, Kitoh H, Ozawa H, Okita S, Harada T, Shiraishi K, Ryozawa S, Okita K (Jan 2003). "Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis". International Journal of Molecular Medicine 11 (1): 33–9. doi:10.3892/ijmm.11.1.33. PMID 12469214.
• Tsai PW, Shiah SG, Lin MT, Wu CW, Kuo ML (Feb 2003). "Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway". The Journal of Biological Chemistry 278 (8): 5750–9. doi:10.1074/jbc.M204863200. PMID 12471041.
• Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, Gill PS (May 2003). "Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops". International Journal of Cancer. Journal International Du Cancer 104 (5): 603–10. doi:10.1002/ijc.10996. PMID 12594815.
• Ohno M, Nakamura T, Kunimoto Y, Nishimura K, Chung-Kang C, Kuroda Y (2004). "Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer". Oncology Reports 10 (4): 939–43. doi:10.3892/or.10.4.939. PMID 12792749.