A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases.
Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The Flt4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the Flt4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds Flt4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where Flt4 is expressed.
Joukov
V
V
Department of Virology, Haartman Institute, University of Helinski, Finland.
Pajusola
K
K
Kaipainen
A
A
Chilov
D
D
Lahtinen
I
I
Kukk
E
E
Saksela
O
O
Kalkkinen
N
N
Alitalo
K
K
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002196:Capillaries; D002417:Cattle; D002460:Cell Line; D002683:Chironomidae; D003001:Cloning, Molecular; D016384:Consensus Sequence; D003545:Cysteine; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D004789:Enzyme Activation; D015870:Gene Expression; D006133:Growth Substances / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010982:Platelet-Derived Growth Factor / Q000737:chemistry; D011471:Prostatic Neoplasms; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D018411:Spodoptera; D014162:Transfection; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
D017931:DNA Primers; D016228:Endothelial Growth Factors; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3; D003545:Cysteine