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The Proteolytic Processing of Pro-Platelet-derived Growth Factor-A at RRKR⁸⁶ by Members of the Proprotein Convertase Family Is Functionally Correlated to Platelet-derived Growth Factor-A-induced Functions and Tumorigenicity¹

Laboratory of Biochemical Neuroendocrinology Clinical Research Institute of Montreal, Montreal, Quebec, H2W 1R7 [G. S., A-M. K., S. B., N. G. S.], and Regional Protein Chemistry Centre, Diseases of Ageing Program, Ottawa Health Research Institute, Ottawa, Ontario, K1Y 4E9 [A-M. K., M. C.] Canada

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 RRKR⁸⁶ to ARKA⁸⁶ 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 2-macroglobulin and 1-antitrypsin. Chinese hamster ovary cells overexpressing pro-PDGF-A (ARKA⁸⁶) failed to induce tumors in nude mice. Thus, PC-directed inhibitors might represent new agents for therapy in neoplasia induced by PDGF-A.

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