A 130-kDa receptor for VEGF165, neuropilin-1 (NRP1), has been purified and expression cloned. NRP1 is a cell surface glycoprotein previously shown to be a receptor for the semaphorins/ collapsins, a family of chemorepulsive proteins that mediate neuronal guidance. NRP1 is expressed by endothelial cells (EC) as are other VEGF receptors (e.g. KDR) but also abundantly by tumor cells, such as breast and prostate carcinoma, where it is the only receptor capable of binding VEGF. Co-expression of NRP1 and KDR in EC results in increased chemotaxis towards VEGF165 when compared to EC expressing KDR alone, suggesting that NRP1 may be a co-receptor for KDR in EC and contribute to angiogenesis. Tumor cells bind VEGF165 and respond by increased motility. Thus, VEGF165 may have a dual function in tumor growth as an angiogenesis factor and as a factor acting directly on tumor cells. While VEGF165 interactions with NRP1 enhance EC motility, collapsin/ semaphorin 111, an inhibitor of axon motility, inhibits EC motility via NRP1 suggesting that these two ligands have opposing effects acting on the same receptor. NRP1, a naturally occurring secreted 90 kDa NRP1 ectodomain (sNRP1) has been cloned which contains a unique intron sequence. Thus, the distribution of sNRP1 can determined by in situ hybridization independent of intact NRP1. SNRP1 is an antagonist of VEGF165 activity. A second gene, NRP2, with 47% homology to NRP1 has been cloned and its properties relative to NRP1 are being investigated. How NRP1 gene expression and activity is regulated is virtually unknown. The overall goals of this proposal are to define the structure, function and regulation of NRP1 as a novel receptor for VEGF165.
The aims of this proposal are: 1) to investigate VEGF165 and semaphorin/collapsin interactions with NRP1; 2) to investigate NRP1 expression and function in tumor cells; 3) to characterize the structure, function and distribution of a naturally occurring soluble NRP1 (sNRP1) receptor and 4) to investigate the regulation of NRP1 gene expression and activity.
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