Vascular endothelial growth factor C (VEGF-C) protein and gene, mutants thereof, and uses thereof
Provided are purified and isolated VEGF-C polypeptides capable of binding to at least one of KDR receptor tyrosine kinase (VEGFR-2) and Flt4 receptor tyrosine kinase (VEGFR-3); analogs of such peptides that have VEGF-C-like or VEGF-like biological activities or that are VEGF or VEGF-C inhibitors; polynucleotides encoding the polypeptides; vectors and host cells that embody the polynucleotides; pharmaceutical compositions and diagnostic reagents comprising the polypeptides; and methods of making and using the polypeptides. Methods of inhibiting endothelial cell proliferation are also provided.
1. An isolated VEGF-C basic polypeptide that comprises an amino acid sequence having at least 95% amino acid identity to a continuous portion of SEQ ID NO: 8 effective to permit binding to human VEGFR-3 and
wherein the continuous portion comprises at least amino acids 131-211 of SEQ ID NO: 8, with the proviso that from one to three residues in the VEGF-C basic polypeptide that correspond to residues 187, 189 and 191 of SEQ ID NO: 8 are a basic amino acid selected from the group consisting of arginine, lysine, and histidine.
2. The isolated VEGF-C basic polypeptide according to claim 1 , wherein the polypeptide comprises an amino acid sequence comprising residues 131 to 211 of SEQ ID NO: 8, wherein the glutamic acid residue at position 187, the threonine residue at position 189, and the proline residue at position 191 of SEQ ID NO: 8 have been replaced by an arginine residue, a lysine residue, and a histidine residue, respectively.
3. A composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.