The proteolytic processing of pro-platelet-derived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity.
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.
Siegfried
Géraldine
G
Laboratory of Biochemical Neuroendocrinology Clinical Research Institute of Montreal, Montreal, Quebec, H2W 1R7, Canada.
Khatib
Abdel-Majid
AM
Benjannet
Suzanne
S
Chrétien
Michel
M
Seidah
Nabil G
NG
D016475:3T3 Cells; D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism; D006224:Cricetinae; D045683:Furin; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000502:physiology; D016133:Polymerase Chain Reaction; D045702:Proprotein Convertase 5; D043484:Proprotein Convertases; D011498:Protein Precursors / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000502:physiology; D013379:Substrate Specificity; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D011498:Protein Precursors; D015842:Serine Proteinase Inhibitors; C075278:platelet-derived growth factor A; D014443:Tyrosine; C080654:PCSK6 protein, human; C513086:Pcsk6 protein, mouse; D045702:Proprotein Convertase 5; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins; C473805:propeptide convertase 5, mouse; D045683:Furin