|
pubmed:abstractText |
Although altered expression of platelet-derived growth factor (PDGF)-A is a hallmark of many cancers, the importance of pro-PDGF-A conversion to PDGF-A in tumorigenesis and the cognate protease(s) is unknown. Pro-PDGF-A processing occurs at pairs of basic residues, likely involving the proprotein convertases (PCs). In the colon carcinoma cell line LoVo, we found that Furin is the most potent PDGF-A convertase. Mutation of the PC-site RRKR(86) to ARKA(86) inhibited pro-PDGF-A processing, its receptor tyrosine phosphorylation, and cell proliferation. This processing is also blocked by the PC preprosegments (pps) ppFurin, ppPC5, and ppPACE4, and by the Furin-variants of alpha2-macroglobulin and alpha1-antitrypsin. Chinese hamster ovary cells overexpressing pro-PDGF-A (ARKA(86)) failed to induce tumors in nude mice. Thus, PC-directed inhibitors might represent new agents for therapy in neoplasia induced by PDGF-A.
|
