%0 Journal Article %J Proc Natl Acad Sci U S A %D 1998 %T Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) %A Achen, M G %A Jeltsch, M %A Kukk, E %A Mäkinen, T %A Vitali, A %A Wilks, A F %A Alitalo, K %A Stacker, S A %X We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs. %B Proc Natl Acad Sci U S A %V 95 %P 548 - 53 %8 1998/Jan/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/9435229 %N 2 %! Proceedings of the National Academy of Sciences of the United States of America %0 Journal Article %J J Biol Chem %D 1997 %T Genomic organization of human and mouse genes for vascular endothelial growth factor C %A Chilov, D %A Kukk, E %A Taira, S %A Jeltsch, M %A Kaukonen, J %A Palotie, A %A Joukov, V %A Alitalo, K %X We report here the cloning and characterization of human and mouse genes for vascular endothelial growth factor C (VEGF-C), a newly isolated member of the vascular endothelial growth factor/platelet-derived growth factor (VEGF/PDGF) family. Both VEGF-C genes comprise over 40 kilobase pairs of genomic DNA and consist of seven exons, all containing coding sequences. The VEGF homology domain of VEGF-C is encoded by exons 3 and 4. Exons 5 and 7 encode cysteine-rich motifs of the type C6C10CRC, and exon 6 encodes additional C10CXCXC motifs typical of a silk protein. A putative alternatively spliced rare RNA form lacking exon 4 was identified in human fibrosarcoma cells, and a major transcription start site was located in the human VEGF-C gene 523 base pairs upstream of the translation initiation codon. The upstream promoter sequences contain conserved putative binding sites for Sp-1, AP-2, and NF-kappaB transcription factors but no TATA box, and they show promoter activity when transfected into cells. The VEGF-C gene structure is thus assembled from exons encoding propeptides and distinct cysteine-rich domains in addition to the VEGF homology domain, and it shows both similarities and distinct differences in comparison with other members of the VEGF/PDGF gene family. %B J Biol Chem %V 272 %P 25176 - 83 %8 1997/Oct/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/9312130 %N 40 %! The Journal of Biological Chemistry %0 Journal Article %J Development %D 1996 %T VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development %A Kukk, E %A Lymboussaki, A %A Taira, S %A Kaipainen, A %A Jeltsch, M %A Joukov, V %A Alitalo, K %X The vascular endothelial growth factor family has recently been expanded by the isolation of two new VEGF-related factors, VEGF-B and VEGF-C. The physiological functions of these factors are largely unknown. Here we report the cloning and characterization of mouse VEGF-C, which is produced as a disulfide-linked dimer of 415 amino acid residue polypeptides, sharing an 85% identity with the human VEGF-C amino acid sequence. The recombinant mouse VEGF-C protein was secreted from transfected cells as VEGFR-3 (Flt4) binding polypeptides of 30-32x10(3) Mr and 22-23x10(3) Mr which preferentially stimulated the autophosphorylation of VEGFR-3 in comparison with VEGFR-2 (KDR). In in situ hybridization, mouse VEGF-C mRNA expression was detected in mesenchymal cells of postimplantation mouse embryos, particularly in the regions where the lymphatic vessels undergo sprouting from embryonic veins, such as the perimetanephric, axillary and jugular regions. In addition, the developing mesenterium, which is rich in lymphatic vessels, showed strong VEGF-C expression. VEGF-C was also highly expressed in adult mouse lung, heart and kidney, where VEGFR-3 was also prominent. The pattern of expression of VEGF-C in relation to its major receptor VEGFR-3 during the sprouting of the lymphatic endothelium in embryos suggests a paracrine mode of action and that one of the functions of VEGF-C may be in the regulation of angiogenesis of the lymphatic vasculature. %B Development %V 122 %P 3829 - 37 %8 1996/Dec/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/9012504 %N 12 %! Development (Cambridge, England)